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Cell Biology International (2009) 33, 453–465 (Printed in Great Britain)
TNF superfamily: Costimulation and clinical applications
Dass S. Vinaya and Byoung S. Kwonbc*
aSection of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
bDepartment of Ophthalmology, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA, USA
cCell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Gyeonggi-Do, Republic of Korea


Abstract

The molecules concerned with costimulation belong either to the immunoglobulin (Ig) or tumor necrosis factor (TNF) superfamily. The tumor necrosis superfamily comprises molecules capable of providing both costimulation and cell death. In this review we briefly summarize certain TNF superfamily receptor–ligand pairs that are endowed with costimulatory properties and their importance in health and disease.


Keywords: TNF superfamily, Costimulation, T cells, Antigen presenting cells, Immune regulation.

*Corresponding author. Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, 111 Jungbalsan-Ro, Ilsan, Goyang, Gyeonggi-Do 410-769, Republic of Korea. Tel.: +82 31 920 2531; fax: +82 31 920 2542.


1 Introduction

Clonal expansion of T cells requires both a ligand which engages its receptor (TcR) and a functionally defined second signal (also called a costimulatory signal). The participation of a costimulatory signal in T cell activation is of paramount importance as it results in two potential outcomes, activation or clonal anergy (Jenkins, 1992; Mueller et al., 1989). The two different outcomes of antigen recognition, by T cells, are first explained by the dual signal model of T cell activation by Bretscher and Cohn (1970). The nature or identity of this accessory signal was initially thought to be a soluble factor but later studies have established that it is a cell surface-derived event and occurs during cognate interaction between an antigen-presenting cell (APC) and partnering T cell (Jenkins and Johnson, 1993).

Based on their molecular structure, the costimulatory molecules have been divided into two major groups belonging either to the immunoglobulin (Ig) or to the tumor necrosis factor (TNF) superfamily. The members of the TNF superfamily have distinctive cytoplasmic death domains and can induce apoptosis as well as receptors with no apparent homology in the cytoplasmic tail. This latter group of receptors is involved in gene activation and anti-apoptotic signaling.

The inventory of the TNF superfamily is increasing rapidly (Fig. 1) and it is impossible to cover all aspects of this superfamily in a short chapter. In this review, as well as briefly summarizing key features about this superfamily, we describe how the well-characterized members of this family concerned with positive immune regulation are coordinated (Fig. 2) and their role in clinical applications.


Fig. 1

Schematic cartoon depicting members of TNF superfamily. Each member of the TNF superfamily is indicated by its scientific nomenclature. The description in the parentheses denotes their common name. Since the expression of a particular TNF receptors or its ligand is not exclusive to a particular cell type and sometimes present on the same cell, a generalized depiction illustrated.


Fig. 2

Schematic representation of important members of TNF superfamily. Although some of the members of the family are constitutively expressed (low levels), in most cases their expression is activation dependent. The expression of given receptor or ligand is not restricted to a particular cell and can sometimes present on both T lymphocyte as well as antigen-presenting cell enabling a bidirectional signaling cascade.



2 CD27–CD70

CD27, a type I disulfide-linked glycoprotein, was discovered more than a decade ago on human resting peripheral blood T cells and medullary thymocytes. Both in humans and mice, CD27 is expressed on naive and memory-type T cells, antigen-primed B cells, and subsets of natural killer (NK) cells (Borst et al., 2005). The CD27 ligand CD70 is transiently and stimulation-dependently expressed on T, B, and dendritic cells (Lens et al., 1997) and constitutively on APCs in the murine intestine (Laouar et al., 2005). Interestingly, CD27 is also expressed by many T cells presumably to modulate the effects of CD70 on B cells by acting as decoy receptors (Hendriks et al., 2000; Kobata et al., 1995).

CD27 costimulation of anti-CD3 primed CD4+ T cells promotes cell division, enhances BcL-xL, and promotes IFN-γ induction (van Oosterwijk et al., 2007). CD27–CD70 signals are important in the terminal differentiation of B cells into antibody-secreting plasma cells (Agematsu et al., 1998; Jacquot et al., 1997; Nagumo et al., 1998). Modulation of the in vivo CD27–CD70 pathway by appropriate agonistic antibodies elicits important functions.

Administration of agonistic anti-CD27 mAbs given without a DC maturation signal completely protects tumor-bearing mice and provides a highly potent reagent for boosting anti-tumor T cell immunity (French et al., 2007). Interestingly, triggering CD27 by its ligand CD70 impedes neutralizing antibody production and leads to persistence of lymphocyte choriomeningitis virus (LCMV) infection (Matter et al., 2006). Treatment with an anti-CD70 antibody has been reported to induce long-term survival of organ allografts in CD28-deficient mice by inhibiting the activation of effector and memory CD8+ T cells (Yamada et al., 2005). This finding suggests that the CD27/70 pathway might be an important target for inhibiting rejection resistant to the blockade of conventional costimulatory molecules. Patients with Waldenstrom macroglobulinemia (WM), a B cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow infiltration with lymphoplasmacytic cells, show elevated soluble CD27 which serves as a marker of disease and as a target in its treatment (Ho et al., 2008). In addition, treatment with engineered anti-CD70 Ab has shown promise as anti-tumor agent (McDonagh et al., 2008; Grewal, 2008).

A salient feature of CD27 is its existence in a soluble form. In vivo levels of serum and urine sCD27 correlate with tumor load in patients with leukemia and lymphoma (Lens et al., 1998; van Oers et al., 1993). High soluble levels of CD27 have also been noted in the synovial fluid of rheumatoid arthritis patients and cerebrospinal fluid of multiple scleorosis patients (van Oers et al., 1993). Although CD27 lacks intrinsic kinase activity (Loenen, 1998), the C-terminal region associates with TRAF2 and 5 that link to NIK and JNK signaling pathways involving the transcription factors NF-κB and Jun (Loenen, 1998). Engagement of CD27 induces a signaling cascade, resulting in activation of NF-κB, promotion of cell survival, and increased T cell effector function (Akiba et al., 1998a; Borst et al., 2005) (Fig. 3). Continuous CD27 signaling, however, leads to T cell depletion (Tesselaar et al., 2003).


Fig. 3

CD27–CD70 pathway. Signaling via CD27–CD70 pathways provides positive immune regulation. When stimulated with appropriate agonist such as anti-CD27 or anti-CD70 or cell lines made to express these molecules relay signals through TRAF2/5 resulting in long-term survival of cells via induction of NIK and NF-κB. Signals also lead to the expression of P13 kinase, ERK1/2, PLCγ leading to robust cell division.


Deletion of endogenous CD27 shows impaired T cell responses to viral infection (Hendriks et al., 2000), but playing a role in germinal center formation (Xiao et al., 2004). Elimination or blockade of the CD27–CD70 pathway with CD27-deficient mice or blocking with anti-CD70 antibody resulted in improved neutralizing antibody responses and clearance and reduction of viral titers, respectively (Matter et al., 2006).

3 CD30–CD153

CD30, originally identified in 1982 on tumor cells of Hodgkin's lymphoma (Schwab et al., 1982), also called Ki-1, is a membrane glycoprotein consisting of two chains with a molecular weight of 120 and 105kDa. It is expressed by a subset of activated T cells (both CD4+ and CD8+), NK, and B cells and is constitutively expressed in decidual and exocrine pancreatic cells with maximum expression on CD45RO+ memory T cells (Annunziato et al., 2000). CD30 expression has been noted on CD4+CD8+ medullary thymocytes, indicating an important role of CD30/CD153 interactions in the thymus.

CD30 ligand (CD30L; CD153) is 26–40kDa protein cloned in 1993 and is present on a variety of cells including activated T cells, macrophages, resting B cells, granulocytes, eosinophils, and neutrophils (Smith et al., 1993). Expression of CD153 was also noted on the outer wall of Hassall's corpuscles and in placenta (Romagnani et al., 1998). As noted in the case of CD27, the soluble form of CD30 (&007E;85/88kDa) is generated when membrane-bound CD30 protein is cleaved by zinc metalloproteinase (Hansen et al., 1995). Interestingly, soluble CD30 (sCD30) shedding can be found in several neoplastic and reactive diseases (Del Prete et al., 1995; Falini et al., 1995; Pizzolo et al., 1994, 1997; Romagnani et al., 1995) but the significance of sCD30 is not clear. In atopic dermatitis, CD30+ infiltrating T cells in lesions, elevated sCD30 levels, and increased number of circulating CD30+ cells were reported (Dummer et al., 2003). Similarly, elevated sCD30 levels and CD30 on BAL γδ+ T cells were noted in atopic asthma (Heshmat and El-Hadidi, 2006). Soluble CD30 was also noted in rhinoconjunctivitis (Bengtsson, 2003). Increased CD30 was also noted in patients with Grave's disease and Hashimoto's thyroiditis (Okumura et al., 1997).

In vitro signaling of CD30 has costimulatory effects on lymphoid cells (Gilfillan et al., 1998). Signaling via CD30 augments proliferation under certain circumstances, but in other cases potentiated apoptosis (Telford et al., 1997) (Fig. 4). In the case of human lymphomas, CD30 signaling reveals reduced proliferation (Lee et al., 1996a). Reports available also suggest that CD30 signals regulate Fas-independent apoptosis in CD8+ T cells (Telford et al., 1997). The CD30 cytoplasmic tail interacts with TRAFs 1, 2, 3, and 5, inducing NF-κB (Aizawa et al., 1997; Duckett and Thompson, 1997; Duckett et al., 1997; Gedrich et al., 1996; Lee et al., 1996b).


Fig. 4

CD30–CD153 pathway. Expression of CD30 or CD153 is not exclusive and can be present on both T cells as well as APCs. Such variable expression pattern of CD130–CD153 results in diverse immune responses. Interaction of CD153 bearing T cell with CD30+ B cell enhances survival gene expression leading to cell division and increased antibody production. On the other hand, CD30+ T cells interaction with CD153+ B cell results in reduced antibody production.


An important role for CD30 in the protection against autoimmune disorders has been reported (Kurts et al., 1999). Unmodified anti-CD30 antibodies as well as anti-CD30-based bispecific antibodies, immunotoxins, and radioimmunoconjugates have been examined in pre-clinical trials and clinical studies. Administration of anti-CD30 coupled to ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma demonstrated only a moderate efficacy (Schnell et al., 2002). The increased expression of CD30 on some neoplasms versus its limited expression on normal tissue makes it an excellent target for antibody therapy. CD30–CD30L interaction also is implicated in the induction of Th2 type immunity (Bowen et al., 1996) but a blockade of CD153 could not abrogate the Th2-directed murine Leishmaniasis (Akiba et al., 2000).

CD30-deficient mice show no abnormality in peripheral immune responses but have a defect in the activation-induced death of thymocytes (Amakawa et al., 1996). MHC class-I and class-II disparate skin and heart grafts are rejected much faster in CD30-deficient mice compared with wild-type mice (Beckmann et al., 2001).

4 CD134–CD134L

CD134 (OX40), one of the most important and widely studied TNF superfamily member, was originally described as a cell surface antigen found on activated rat T cells (Paterson et al., 1987). OX40 is transiently expressed following T cell ligation of the TCR and its ligand OX40L (CD252) is expressed on APCs and endothelium. Although CD134 is present on a variety of cells, its role in T cell activation has been thoroughly investigated (So et al., 2008; Sugumura et al., 2004; Weinberg, 2002). The ligand for CD134 (CD134L) was originally termed glycoprotein 34 (gp34) and was identified on human T-leukemia virus type 1 transformed cells (Akiba et al., 1998b).

Signals via OX40 are costimulatory in nature (Watts, 2005) and support late immune responses, enabling effective long-lasting T cell response (Croft, 2003; Salek-Ardakani and Croft, 2006; Weinberg et al., 2004) leading to T cell division, survival, and cytokine induction (Gramaglia et al., 2000; Maxwell et al., 2000; Rogers et al., 2001; Weinberg, 1998; Weinberg et al., 1999) (Fig. 5). The validity of these findings was further substantiated by the determination that in OX40-deficient mice the T helper responses were greatly diminished, while the B cell and CTL responses remained unaffected (Kopf et al., 1999). Also, studies with OX40-Ig fusion protein demonstrate decreased T cell responses under the conditions tested (Weinberg et al., 1999). On the other hand, OX40 signals inhibit Treg cell development and function (So and Croft, 2007; Kroemer et al., 2007; Watts, 2005). Signals via OX40 are relayed through TRAF2, TRAF3, and TRAF5, resulting in NF-κB activation (Arch and Thompson, 1998; Kawamata et al., 1998).


Fig. 5

CD134–CD134L pathway. CD134 is transiently expressed on T cells and is known to support late immune responses. Once expressed and when stimulated via TCR or agonistic anti-CD134 mAbs or cells made to express CD134L supports cell division and IL-2 production resulting in long-tern survival of memory T cells.


The importance of the OX40–OX40L pathway in health and disease has been extensively explored (Hori, 2006; Kaleeba et al., 1999; Weinberg et al., 1996, 2004). The first description of enhanced responses through exploitation of the OX40–OX40L pathway was made using OX40L fusion proteins and anti-OX40 mAbs in a tumor model (Pan et al., 2002; Weinberg et al., 2000). OX40 dependent costimulation enhances EAE and is involved in promoting atherosclerotic disease (Gotsman et al., 2008). The role of OX40 signaling is important for allograft response (Demirci and Li, 2008), anti-viral responses (Bertram et al., 2004), and autoimmune processes and cancer (Redmond and Weinberg, 2007). The significance of the OX40 pathway is also explored in allergic reactions (Kroczek and Hamelmann, 2005). Allergen-sensitized and challenged OX40L-deficient mice showed decreased airway hyperactivity, Th2 cytokine production, and serum IgE levels (Arestides et al., 2002).

Besides its role in costimulation of CD4 cells, OX40/OX40L interactions are closely involved in effector functions as well. For example, OX40L cross-linking supported B cell stimulation and antibody production (Stuber et al., 1995), and elevated dendritic cell effector functions (Ohshima et al., 1997). Interfering with this association can inhibit both primary and secondary IgG responses (Stuber and Strober, 1996).

5 CD137–CD137L

Another important and extensively studied member of the TNF superfamily is the CD137 (4-1BB)–CD137L (4-1BBL) (Vinay and Kwon, 2006). CD137 was initially discovered in screens for receptors on activated mouse lymphocytes (Kwon and Weismann, 1989). The CD137 is not detected (<3%) on resting T cells and T cell lines. However, when the T cells, in the presence of APCs, are stimulated with a variety of agonists (plate-bound anti-CD3, concanavalin A, phytohemagglutinin, IL-2, IL-4, anti-CD28, PMA, ionomycin alone or in combinations) CD137 upregulates and maintains its expression (Pollok et al., 1993). Interestingly, expression of CD137 is detectable on CD11c+ dendritic cells and CD4+CD25+ Tregs of naïve mice (McHugh et al., 2002; Wilcox et al., 2002). In vitro the CD137 signal provides costimulatory signals to T cells and shows preference for CD8 over CD4 T cells, leading to cellular proliferation, IL-2 production, and increased expression of survival genes (Vinay et al., 2006b). Signals by CD137 are relayed through TRAF1, TRAF2, and TRAF3, which interact with the cytoplasmic domain of CD137; mutation analysis showed the involvement of the runs of acidic residues in the cytoplasmic domain of CD137 (Jang et al., 1998). Jang et al. (1998) and Arch and Thompson (1998) reported that CD137 cross-linking induces activation of NF-κB and is inhibited by dominant negative TRAF2 and NF-κB-inducing kinase (NIK). CD137 is secreted in soluble form in sera and lymphocyte secretions in patients with rheumatoid arthritis (Michel et al., 1998). CD137 shares this feature with certain other receptor forms, such as TNFR, NGFR, CD27, CD30, and CD95.

Interestingly, in vivo administration of agonistic antibodies supports robust CD8+ T cell expansion and shrinking of CD4 and B cell numbers and humoral immunity (Vinay et al., 2006a). In depth analysis revealed increased in vivo production of IFN-γ, TNF-α, and TGF-β in anti-CD137 treated animals to be perpetuators of dampened CD4 and humoral responses (Niu et al., 2007; Menoret et al., 2006; Myers et al., 2005; Sun et al., 2002; Vinay et al., 2006a). Others have advocated that in vivo anti-CD137 Abs increases IFN-γ in CD8+ T cells, which in turn upregulate indoleamine 2,3-dioxygenase (IDO) in competent APCs which when interacting with CD4+ T cells, bring about their destruction (Choi et al., 2006; Seo et al., 2004) (Fig. 6). Seo et al. (2004) have demonstrated that anti-CD137 mAbs expands a novel CD11c+CD8+ population expressing high levels of IFN-γ and adoptive transfer of these CD11c+CD8+ T cells into susceptible mice ameliorate arthritis. Agonistic anti-CD137 Abs has potent anti-tumor properties and increases transplant survival and anti-viral properties (Croft, 2003; Vinay et al., 2006b).


Fig. 6

CD137–CD137L pathway. With a few exceptions expression of CD137 is activation dependent. There is a variability in anti-CD137-mediated signaling. While in vitro anti-CD137 stimulation supports activation of both CD4+ and CD8+ T cells, in vivo effects mediated by anti-CD137 is complex. Administration of agonistic anti-CD137 mAbs supports robust CD8+ T cell expansion and constricts CD4+ T and B cell numbers and function. This latter in vivo effect of anti-CD137 is believed to result from over expression of IFN-γ, IL-10, TGF-β, granzymeB, perforin, and CTLA-4 and expansion of a novel immunoregulatory CD11c+CD8+ T cell subset. The increased IFN-γ due to anti-mediated CD11c+CD8+ T cells upregulates indoleamine 2,3-dioxygenase (IDO) in competent cells which when interact with partnering CD4+ T cells causes their deletion. This can be reversed by neutralizing IDO activity by 1-methyltryptophan.


6 CD40–CD154

The CD40 pathway remains the most extensively studied TNF superfamily members. The amount of research data available and its success as a therapeutic agent are too vast to cover in this review. CD40 was first identified in 1985 on B cells (Paulie et al., 1985). CD40 received its definition at the 3rd International CD Workshop (Stamenkovic et al., 1989). CD154 (CD40L, gp39, T-Bam or TRAP) is an activation-induced molecule present on CD4+ T cells, monocytes, DCs, and a small proportion of CD8+ cells (Schonbeck and Libby, 2001). The role of CD40 in the regulation of B cell biology is well documented (D'Orlando et al., 2007; Quezada et al., 2004). Besides B cells, CD40 is also present on a variety of antigen-presenting cells; non-antigen-presenting cells including dendritic cells; follicular dendritic cells; monocytes; macrophages; mast cells; fibroblasts; epithelial cells; vascular smooth muscle cells and endothelial cells; and as a functional molecule on CD4+ T cells (Grewal and Flavell, 1998; Munroe and Bishop, 2007) (Fig. 7).


Fig. 7

CD40–CD154 pathway. Expression of CD40 is widespread on a variety of cells including CD4+ T cells. CD40 binds to an activation-induced CD154 molecule. Interaction of CD154+ CD4+ T cells with CD40-bearing cells results in the activation of partnering cells resulting in expression of cell survival genes, cytokine induction, Ig isotype switching, etc.


CD4–CD154 interactions mediate one of the most effective APC-activating signals. Signaling via the dendritic cell CD40 molecule upregulates expression of CD80 and CD86, and induces IL-12 secretion (Cella et al., 1996; Ridge et al., 1998; Schuurhuis et al., 2000). Signaling via CD40 activates NF-κB (Lalmanach-Girard et al., 1993; Berberich et al., 1994) and rescues BCR-induced cell death (Schauer et al., 1996). Moreover, the CD40–CD154 pathway is central to germinal center formation and Ig isotype switch as validated by studies using CD40−/− mice (Kawabe et al., 1994).

In vivo, CD40 ligation supports CD4+ and CD8+ T cell growth, resulting in increase in tumor protection and alteration of steady-state tolerance into immunity (Bonifaz et al., 2002; Clarke, 2000; Diehl et al., 1999; French et al., 1999; Lefrancois et al., 2000; Mackey et al., 1998; Toes et al., 1998). On the other hand, the CD40-signaling blockade, mainly through anti-CD40L Ab, inhibits T cell activation and results in tolerance, e.g., to transplants, and control of some autoimmune diseases (Diehl et al., 2000; Iwakoshi et al., 2000). Blockade of the CD40–CD154 pathway has been proven beneficial in transplantation (Bishop, 2002; Mungara et al., 2008; Nathan et al., 2002) and autoimmune diseases (Toubi and Shoenfeld, 2004).

7 GITR–GITRL

The glucocorticoid-induced tumor necrosis factor receptor (GITR) family-related gene was cloned first from dexamethasone-treated murine T cell hybridoma (3DO) cells using a differential display technique (Nocentini et al., 1997, 2000a). Two groups identified that a novel 25kDa protein named activation-inducible protein of the TNF receptor (AITR) is the human homolog of the murine GITR (Gurney et al., 1999; Kwon et al., 1999). The AITR, which has 55% identity with murine GITR at the amino acid level, is activated by transducing signals through a TRAF2-mediated mechanism. The expression of AITR is inducible by PMA and ionomycin, anti-CD3 plus anti-CD28 monoclonal antibodies. It is detected as a 1.25kb mRNA in lymph nodes, PBLs and weakly in the spleen and colorectal adenocarcinoma cell line (SW 480) (Kwon et al., 1999). GITR is a 228 amino acid type I transmembrane protein characterized by three cysteine pseudorepeats in the extracellular domain. It is similar to CD137 in the intracellular domain. The full-length GITR cDNA revealed a 1005bp long sequence. Northern blot analysis suggested that GITR mRNA is about 1.1kb long. Subsequent studies showed at least three spliced variants of GITR (Nocentini et al., 2000b).

GITR is not detectable in freshly derived lymphoid tissues (including thymocytes, spleen, and lymph node T cells), liver, kidney, and brain and T cell hybridoma 3DO. However, low levels of GITR mRNA were detected by competitive RT-PCR in T cell hybridoma, thymocytes, spleen, and lymph node T cells. GITR expression in T cells was found to increase 4- to 8-fold upon treatment with immobilized anti-CD3 and Con A and PMA. However, the induction of kinetics was slow with no increase before 6h (Nocentini et al., 1997). The murine GITR ligand was cloned and characterized in 2003 (Kim et al., 2003). These authors demonstrated that GITRL is detected on immature and mature dendritic cells. In addition, GITRL binding GITR on HEL 293 cells triggers NF-κB activation and the addition of soluble GITRL prevents CD25+CD4+ Treg-mediated suppressive activities (Kim et al., 2003).

Signaling via GITR is costimulatory in nature (Nocentini and Riccardi, 2005). McHugh et al. (2002) were the first to demonstrate that GITR is constitutively expressed on CD25+CD4+ Tregs. Simultaneously, Shimizu et al. (2002) determined that GITR plays a key role in dominant immunological self-tolerance maintained by CD25+CD4+ regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease (Fig. 8). Interestingly, macrophages were shown to express constitutively both GITR and GITRL and stimulation of these cells with recombinant soluble GITRL results in increased nitric oxide synthase, cyclooxygenase-2 protein, generated significant amounts of prostaglandin E2, and matrix metalloproteinase 9 (Lee et al., 2003; Shin et al., 2000, 2002, 2003).


Fig. 8

GITR–GITRL pathway. Expression of GITR is activation dependent with the exception of Foxp3+ Tregs which express this antigen in a constitutive manner. Signals through GITR are costimulatory in nature to CD4+ and CD8+T cells resulting in cell division and cytokine induction. Importantly GITR provides key signals to Foxp3+ Tregs to maintain immune tolerance and plays a critical role in the control of autoimmune diseases.


Signaling through GITR induces NF-κB activation mediated by TRAF4 and is inhibited by the cytoplasmic protein A20 (Esparza and Arch, 2004). Anti-GITR Ab therapy significantly increased disease severity in an EAE model (Kohm et al., 2004).

The importance of the GITR pathway has begun to be appreciated (Nocentini and Riccardi, 2005). GITR knockout mice develop normally but show increased cell proliferation, IL-2 receptor expression, and IL-2 production compared with control wild-type mice in cultures stimulated with anti-CD3 (Ronchetti et al., 2002). Patients with non-infectious uveitis show more GITR+CD4+ T cells than normal individuals (Li et al., 2003). Treatment of SJL mice with anti-GITR antibody in conjunction with proteolipid protein (PLP 131–151) significantly exacerbated clinical disease severity and CNS inflammation. On the other hand, prior depletion of CD25+CD4+ Tregs failed to result in EAE, suggesting alternative targets for the anti-GITR Ab treatment (Kohm et al., 2004). Administration of anti-GITR Ab in 3-month-old mice results in autoimmune gastritis associated with anti-parietal cell auto-antibodies (Shimizu et al., 2002). In addition, the importance of the GITR–GITRL pathway is underscored in several models including colitis (Uraushihara et al., 2003), autoimmune diabetes (Suri et al., 2004), GVHD (Muriglan et al., 2004), shock due to splanchnic artery occlusion (Cuzzocrea et al., 2004), viral infections (Dittmer et al., 2004), and cancer (Calmels et al., 2005).

8 HVEM–LIGHT

Herpes virus entry mediator (HVEM) was identified and cloned in 1996 as one of many entry receptors for α-herpesviruses (Montgomery et al., 1996). HVEM has a wide tissue distribution (Kwon et al., 1997) and is present on a variety of cell types including T and B cells, monocytes, and DCs (Harrop et al., 1998a; Morel et al., 2001).

LIGHT, a 29kDa type II transmembrane protein, was identified as a ligand for HVEM (Mauri et al., 1998). Although HVEM binds LIGHT, it also binds LTα3 and LIGHT besides binding HVEM, also binds LTRβ, thus complicating the interpretations (Croft, 2003) (Fig. 9). LIGHT is expressed by several cell types, including T cells and DCs (Morel et al., 2000; Tamada et al., 2000a). LIGHT signaling leads to T cell growth and differentiation and has CD28-independent costimulatory activity (Tamada et al., 2000b). LIGHT signaling is important for CD8+ T cell-mediated allo-responses (Liu et al., 2003; Scheu et al., 2002). Transgenic expression of LIGHT in T cells results in acute intestinal inflammation, increased production serum IgA, kidney IgA deposition, and exacerbation of nephritis (Wang et al., 2004).


Fig. 9

HVEM–LIGHT pathway. HVEM was originally identified as entry mediator of herpes virus. HVEM signaling is complex as it binds KIGHt as well as LTα3 and is further complicated as LIGHT besides binding HVEM also binds LTRβ. This complex receptor–ligand interactions as well as HSV–HVEM interplay culminate array of signaling molecules, type IIFNs, etc.


HVEM stimulation by LIGHT leads to costimulation of T cells and DC activation (Morel et al., 2000; Tamada et al., 2000a). The importance of HVEM in immune regulation was demonstrated in tumor rejection (Tamada et al., 2000b), GVHD (Tamada et al., 2000b, 2002), autoimmune diseases (Shaikh et al., 2000; Wang et al., 2001), and atherosclerosis (Lee et al., 2001). Blockade of LIGHT was shown to hamper early T cell proliferation and cytokine secretion in MLR reaction (Kwon et al., 1997; Harrop et al., 1998b; Tamada et al., 2000a). LIGHT induces apoptosis in tumor cells expressing both LTβR and HVEM, especially when combined with IFN-γ (Mauri et al., 1998; Harrop et al., 1998a; Rooney et al., 2000). The human immunodeficiency virus-1 (HIV-1 Nef) increases expression of LIGHT, resulting in heightened cytokine activity leading to disease progression in infected individuals (Lama and Ware, 2000). Overexpression of LIGHT in MDA-MB-231 breast cancer cells suppressed tumor growth (Zhai et al., 1998).

In summary, the last few years have seen rapid growth in the number of members of TNF superfamily. Exploitation of the various unique biological functions of the TNF superfamily members for therapeutic use have shown promise. Further research in this area will undoubtedly unravel keys to effective therapeutic intervention in cancer, transplant survival, anti-viral effectiveness, and autoimmunity.

Acknowledgements

This work was supported by grants from the National Cancer Center, Korea (NCC-0890830-2 and NCC-0810720-2); Korean Research Foundation (KRF-2005-084-E00001); Korean Science and Engineering Foundation (Stem Cell-M10641000040 and Discovery of Global New Drug-M10870060009); Korea Health 21 R&D (A050260); NIH RO1-EY013325, LSU Eye Center Core Grant for Vision Research NIH EY02377; Arthritis Foundation (Innovative Research Award). The LSUHSC Department of Ophthalmology has an unrestricted grant from Research to Prevent Blindness, New York, New York and receives funding from the Louisiana Lions Eye Foundation.

References

Agematsu K, Nagumo, H, Oguchi, Y, Nakazawa, T, Fukushima, K, Yasui, K. Generation of plasma cells from peripheral blood memory B cells: synergistic effect of interleukin-10 and CD27/CD70 interaction. Blood 1998:91:173-80
Medline   1st Citation  

Aizawa S, Nakano, H, Ishida, T, Horie, R, Nagai, M, Ito, K. Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NF-κB activation. J Biol Chem 1997:272:2042-5
Crossref   Medline   1st Citation  

Akiba H, Nakano, H, Nishinaka, S, Shindo, M, Kobata, T, Atsuta, M. CD27, a member of the necrosis factor receptor superfamily, activates NF-κB and stress-activated protein-kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-κB inducing kinase. J Biol Chem 1998:273:13353-8
Crossref   Medline   1st Citation  

Akiba H, Atsuta, M, Yagita, H, Okumura, KO. Identification of rat OX40 ligand by molecular cloning. Biochem Biophys Res Commun 1998:251:131-6
Crossref   Medline   1st Citation  

Akiba H, Miyahira, Y, Atsuta, M, Takeda, K, Nohara, C, Futagawa, H. Critical contribution of OX ligand to T helper cell type differentiation in experimental Leishmaniasis. J Exp Med 2000:191:375-80
Crossref   Medline   1st Citation  

Amakawa R, Hakem, A, Kundig, TM, Matsuyama, T, Simard, JJ, Timms, E. Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice. Cell 1996:84:551-62
Crossref   Medline   1st Citation  

Annunziato F, Romagnani, P, Mavilia, C, Pizzolo, G, Stein, H, Romagnani, S. CD30. Cytokine ref 2000:1669-84
1st Citation  

Arch RH, Thompson, CB. 4-1BB and OX-40 are members of tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor κB. Mol Cell Biol 1998:18:558-65
Medline   1st Citation   2nd  

Arestides RS, He, H, Westlake, RM, Chen, AI, Sharpe, AH, Perkin, DL. Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation. Eur J Immunol 2002:32:2874-80
Crossref   Medline   1st Citation  

Beckmann J, Kurts, C, Klebba, I, Bayer, B, Klempnauer, J, Hoffmann, MW. The role of CD30 in skin and heart allograft rejection in the mouse. Transplant Proc 2001:33:140-1
Crossref   Medline   1st Citation  

Bengtsson A. The role of CD30 in atopic diseases. Allergy 2003:56:593-603
Crossref   1st Citation  

Berberich I, Shu, GL, Clark, EA. Cross-linking CD40 on B cells rapidly activates nuclear factor-kappa B. J Immunol 1994:153:4357-66
Medline   1st Citation  

Bertram EM, Dawicki, W, Watts, TH. Role of T cell costimulation in anti-viral immunity. Semin Immunol 2004:16:185-96
Crossref   Medline   1st Citation  

Bishop DK. The immunobiology of inductive anti-CD40L therapy in transplantation: allograft acceptance is not dependent upon the deletion of graft-reactive T cells. Am J Transplant 2002:2:323-32
Crossref   Medline   1st Citation  

Bonifaz L, Bonnyay, D, Mahnke, K, Rivera, M, Nussenzweig, MC, Steinman, RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on majorhistocompatibility complex class I products and peripheral CD8− T cell tolerance. J Exp Med 2002:196:1627-38
Crossref   Medline   1st Citation  

Borst J, Hendriks, J, Xiao, Y. CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol 2005:17:275-81
Crossref   Medline   1st Citation   2nd  

Bowen MA, Lee, RK, Miragliotta, G, Nam, SY, Podack, ER. Structure and expression of murine CD30 and its role in cytokine production. J Immunol 1996:156:442-9
Medline   1st Citation  

Bretscher P, Cohn, M. Paralysis and induction involve the recognition of one and two determinants of an antigen, respectively. Science 1970:169:1042-9
Crossref   Medline   1st Citation  

Calmels B, Paul, S, Futin, N, Ledoux, C, Stoeckel, F, Acres, B. Bypassing tumor-associated immune suppression with recombinant adenovirus constructs expressing membrane bound or secreted GITR-L. Cancer Gene Ther 2005:12:198-205
Crossref   Medline   1st Citation  

Cella M, Scheidegger, D, Palmer-Lehmann, K, Lane, P, Lanzavecchia, A, Alber, G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation. J Exp Med 1996:184:747-52
Crossref   Medline   1st Citation  

Choi BK, Asai, T, Vinay, DS, Kim, YH, Kwon, BS. 4-1BB-mediated amelioration of experimental autoimmune uveoretinitis is caused by indoleamine 2,3-dioxygenase dependent mechanisms. Cytokine 2006:34:233-42
Crossref   Medline   1st Citation  

Clarke SR. The critical role of CD40/CD40L in the CD4-dependent generation of CD8+ T cell immunity. J Leukoc Biol 2000:67:607-14
Medline   1st Citation  

Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity. Nat Rev Immunol 2003:3:600-20
1st Citation   2nd   3rd  

Cuzzocrea S, Nocentini, G, Di Paola, R, Mazzon, E, Ronchetti, S, Genovese, T. Glucocorticoidinduced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock. J Leukoc Biol 2004:76:933-40
Crossref   Medline   1st Citation  

D'Orlando O, Gri, G, Cattaruzi, G, Merluzzi, Betto E, Gattei, V, Pucillo, C. Outside inside signaling in CD40-mediated B cell activation. J Biol Regul Homeost Agents 2007:21:49-62
Medline   1st Citation  

Del Prete G, Izzolo, ME, Romagnani, S. CD30, Th2 cytokines and HIV infection; a complex and fascinating link. Immunol Today 1995:16:76-80
Crossref   Medline   1st Citation  

Demirci G, Li, XC. Novel roles of OX40 in the allograft response. Curr Opin Organ Transplant 2008:13:26-30
Crossref   Medline   1st Citation  

Diehl L, den Boer, AT, Schoenberger, SP, van der Voort, EI, Schumacher, TN, Melief, CJ. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 1999:1999:5:774-9
1st Citation  

Diehl L, den Boer, AT, van der Voort, EI, Melief, CJ, Offringa, R, Toes, RE. The role of CD40 in peripheral T cell tolerance and immunity. J Mol Med 2000:78:363-71
Crossref   Medline   1st Citation  

Dittmer U, He, H, Messer, RJ, Schimmer, S, Olbrich, AR, Ohlen, C. Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity 2004:20:293-303
Crossref   Medline   1st Citation  

Duckett CS, Thompson, CB. CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signalling and the control of cell survival. Genes Dev 1997:11:2810-21
Crossref   Medline   1st Citation  

Duckett CS, Gedrich, RW, Gilfillan, MC, Thompson, CB. Induction of nuclear factor κB by the CD30 receptor is mediated by TRAF1 and TRAF2. Mol Cell Biol 1997:17:1535-42
Medline   1st Citation  

Dummer W, Brocker, EB, Bastian, BC. Elevated serum levels of soluble CD30 are associated with atopic dermatitis, but not with respiratory disorders and allergic contact dermatitis. Br J Dermatol 2003:137:185-7
Crossref   1st Citation  

Esparza EM, Arch, RH. TRAF4 functions as an intermediate of GITR-induced NF-kappaB activation. Cell Mol Life Sci 2004:61:3087-92
Crossref   Medline   1st Citation  

Falini B, Pileri, S, Pizzolo, G, Dürkop, H, Flenghi, L, Stirpe, F. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood 1995:85:1-14
Medline   1st Citation  

French RR, Chan, HT, Tutt, AL, Glennie, MJ. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 1999:5:548-53
Crossref   Medline   1st Citation  

French RR, Taraban, VY, Crowther, GR, Rowley, TF, Gray, JC, Johnson, PW. Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood 2007:109:4810-5
Crossref   Medline   1st Citation  

Gedrich RW, Gilfillan, MC, Duckett, CS, Van Dongen, JL, Thompson, CB. CD30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor-associated factor family of signal transducing proteins. J Biol Chem 1996:271:12852-8
Crossref   Medline   1st Citation  

Gilfillan MC, Noel, PJ, Podack, ER, Reiner, SL, Thompson, CB. Expression of the costimulatory receptor CD30 is regulated by both CD28 and cytokines. J Immunol 1998:160:2180-7
Medline   1st Citation  

Gotsman I, Sharpe, AH, Lichtman, AH. T-cell costimulation and coinhibition in atherosclerosis. Circ Res 2008:103:1220-31
Crossref   Medline   1st Citation  

Gramaglia I, Cooper, D, Miner, KT, Kwon, BS, Croft, M. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol 2000:165:3043-50
Medline   1st Citation  

Grewal IS. CD70 as a therapeutic target in human malignancies. Expert Opin Ther Targets 2008:12:341-51
Crossref   Medline   1st Citation  

Grewal I, Flavell, RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998:16:111-35
Crossref   Medline   1st Citation  

Gurney AL, Marsters, SA, Huang, RM, Pitti, RM, Mark, DT, Baldwin, DT. Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr Biol 1999:9:215-8
Crossref   Medline   1st Citation  

Hansen HP, Kisseleva, T, Kobarg, J, Horn-Lohrens, O, Havsteen, B, Lemke, HA. Zinc metalloproteinase is responsible for the release of CD30 on human tumor cell lines. Int J Cancer 1995 Nov 27:63:5:750-6
Crossref   Medline   1st Citation  

Harrop JA, McDonnell, PC, Brigham-Burke, M, Lyn, SD, Minton, J, Tan, KB. Herpes virus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J Biol Chem 1998:273:27548-56
Crossref   Medline   1st Citation   2nd  

Harrop JA, Reddy, M, Dede, K, Brigham-Burke, M, Ly, S, Tan, KB. Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J Immunol 1998:1998:161:1766-94
1st Citation  

Hendriks J, Loes, A, Gravestein, LA, Tesselaar, K, van Lier, RA, Schumacher, TN. CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol 2000:1:433-40
Crossref   Medline   1st Citation   2nd  

Heshmat NM, El-Hadidi, ES. Soluble CD30 serum levels in atopic dermatitis and bronchial asthma and its relationship with disease severity in pediatric age. Pediatric Allergy Immunol 2006:17:297-303
Crossref   1st Citation  

Ho AW, Hatjiharissi, E, Ciccarelli, BT, Branagan, AR, Hunter, ZR, Leleu, X. CD27–CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia. Blood 2008:112:4683-90
Crossref   Medline   1st Citation  

Hori T. Role of OX40 in the pathogensis and control of diseases. Int J Hematol 2006:83:17-22
Crossref   Medline   1st Citation  

Iwakoshi NN, Mordes, JP, Markees, TG, Phillips, NE, Rossini, AA, Greiner, DL. Treatment of allograft recipients with donor-specific transfusion and anti-CD154 antibody leads to deletion of alloreactive CD8+ T cells and prolonged graft survival in a CTLA4-dependent manner. J Immunol 2000:164:512-21
Medline   1st Citation  

Jacquot S, Kobata, T, Iwata, S, Morimoto, C, Schlossman, SF. CD154/CD40 and CD70/CD27 interactions have different and sequential functions in T cell-dependent B cell responses: enhancement of plasma cell differentiation by CD27 signaling. J Immunol 1997:159:2652-7
Medline   1st Citation  

Jang IK, Lee, ZH, Kim, YJ, Kim, SH, Kwon, BS. Human 4-1BB signals are mediated by TRAF2 and activate nuclear factor-κB (NF-κB). Biophys Biochem Res Commun 1998:242:613-20
Crossref   1st Citation   2nd  

Jenkins MK. The role of cell division in the induction of clonal anergy. Immunol Today 1992:13:69-73
Crossref   Medline   1st Citation  

Jenkins MK, Johnson, JG. Molecules involved in T-cell costimulation. Curr Opin Immunol 1993:5:361-7
Crossref   Medline   1st Citation  

Kaleeba JA, Offner, H, Vandenbark, AA, Lublinski, A, Weinberg, AD. Ox-40 receptor provides a potent co-stimulatory signal capable of inducing encephalitogenicity in myelin-specific CD4+ T cells. Int. Immunol 1999:10:453-61
1st Citation  

Kawabe T, Naka, T, Yoshida, K, Tanaka, T, Fujiwara, H, Suematsu, S. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994:1:167-78
Crossref   Medline   1st Citation  

Kawamata S, Hori, T, Imura, A, Takaori-Kondo, A, Uchiyama, T. Activation of Ox-40 signal transduction pathways lead to tumor necrosis factor receptor-associated factor (TRAF)-2 and -5 mediated NF-kappaB activation. J Biol Chem 1998:273:5808-14
Crossref   Medline   1st Citation  

Kim JD, Choi, BK, Bae, JS, Lee, UH, Han, IS, Lee, HW. Cloning and characterization of GITR ligand. Genes Immun 2003:4:564-9
Crossref   Medline   1st Citation   2nd  

Kobata T, Jacquot, S, Kozlowski, S, Agematsu, K, Schlossman, SF, Morimoto, C. CD27–CD70 interactions regulate B-cell activation by T cells. Proc Natl Acad Sci U S A 1995:92:11249-53
Crossref   Medline   1st Citation  

Kohm AP, Williams, JS, Miller, SD. Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis. J Immunol 2004:172:4686-90
Medline   1st Citation   2nd  

Kopf M, Ruedl, C, Schmitz, N, Gallimore, A, Lefrang, K, Ecabert, B. Ox-40-deficient mice are defective in Th cell proliferation but are competent in generating B cell and CTL responses after virus infection. Immunity 1999:11:699-708
Crossref   Medline   1st Citation  

Kroczek R, Hamelmann, E. T-cell costimulatory molecules: optimal targets for the treatment of allergic airway disease with monoclonal antibodies. J Allergy Clin Immunol 2005:116:906-9
Crossref   Medline   1st Citation  

Kroemer A, Xiao, X, Vu, MD, Gao, W, Minamimura, K, Chen, M. OX40 controls functionally different T cell subsets and their resistance to depletion therapy. J Immunol 2007:179:5584-91
Medline   1st Citation  

Kurts C, Carbon, FR, Krummel, MF, Koch, KM, Miller, JFAP, Heath, WR. Signalling through CD30 protects against autoimmune diabetes mediated by CD8T cells. Nature 1999:398:341-4
Crossref   Medline   1st Citation  

Kwon BS, Weismann, SM. cDNA sequences of two inducible T-cell genes. Proc Natl Acad Sci U S A 1989:86:1963-7
Crossref   Medline   1st Citation  

Kwon BS, Tan, KB, Ni, J, Oh, KO, Le, ZH, Kim, KK. A newly identified member of the TNF superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem 1997:272:14272-6
Crossref   Medline   1st Citation   2nd  

Kwon B, Yu, KY, Ni, J, Yu, GL, Jang, IK, Kim, YJ. Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand. J Biol Chem 1999:274:6056-61
Crossref   Medline   1st Citation   2nd  

Lalmanach-Girard AC, Chiles, TC, Parker, DC, Rothstein, TL. T cell-dependent induction of NF-kappa B in B cells. J Exp Med 1993:177:1215-9
Crossref   Medline   1st Citation  

Lama J, Ware, CF. Human immunodeficiency virus type 1Nef mediates sustained membrane expression of tumor necrosis factor and the related cytokine LIGHT on activated T cells. J Virol 2000:74:9396-402
Crossref   Medline   1st Citation  

Laouar A, Haridas, V, Vargas, D, Zhinan, X, Chaplin, D, van Lier, RA. CD70+ antigen-presenting cells control the proliferation and differentiation of T cells in the intestinal mucosa. Nat Immunol 2005:6:698-706
Crossref   Medline   1st Citation  

Lee SY, Park, CG, Choi, Y. T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors. J Exp Med 1996:183:669-74
Crossref   Medline   1st Citation  

Lee SY, Lee, SY, Kandala, G, Liou, ML, Liou, HC, Choi, Y. CD30/TNF receptor-associated factor interaction: NF-κB activation and binding specificity. Proc Natl Acad Sci U S A 1996:93:9699-703
Crossref   Medline   1st Citation  

Lee WH, Kim, SH, Lee, BB, Kwon, B, Song, H, Kwon, BS. TNFRSF14 is involved in atherogenesis by inducing pro-inflammatory cytokines and matrix matalloproteinases. Arterioscler Thromb Vasc Biol 2001:21:2004-10
Crossref   Medline   1st Citation  

Lee HS, Shin, HH, Kwon, BS, Choi, HS. Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR) increased MMP-9 activity in murine macrophage. J Cell Biochem 2003:88:1048-56
Crossref   Medline   1st Citation  

Lefrancois L, Altman, JD, Williams, K, Olson, S. Soluble antigen and CD40 triggering are sufficient to induce primary and memory cytotoxic T cells. J Immunol 2000:164:725-32
Medline   1st Citation  

Lens SM, Baars, PA, Hooibrink, B, Van Oers, MH, Van Lier, RA. Antigen-presenting cell-derived signals determine expression levels of CD70 on primed T cells. Immunology 1997:90:38-45
Crossref   Medline   1st Citation  

Lens SM, Tesselaar, K, van Oers, MH, Van Lier, RA. Control of lymphocyte function through CD27–CD70 interactions. Semin Immunol 1998:10:491-9
Crossref   Medline   1st Citation  

Li Z, Mahesh, SP, Kim, BJ, Buggage, RR, Nussenblatt, RB. Expression of glucocorticoid induced TNF receptor family related protein (GITR) on peripheral T cells from normal human donors and patients with non-infectious uveitis. J Autoimmun 2003:21:83-92
Crossref   Medline   1st Citation  

Liu J, Schmidt, CS, Zhao, F, Okragly, AJ, Glasebrook, A, Fox, N. LIGHT-deficiency impairs CD8+ T cell expansion, but not effector function. Int Immunol 2003:15:861-70
Crossref   Medline   1st Citation  

Loenen WA. CD27 and (TNFR) relatives in the immune system: their role in health and disease. Semin Immunol 1998:10:417-22
Crossref   Medline   1st Citation   2nd  

Mackey MF, Barth, RJ, Noelle, RJ. The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells. J Leukoc Biol 1998:63:418-28
Medline   1st Citation  

Matter M, Odermatt, B, Yagita, H, Nuoffer, JM, Ochsenbein, AF. Elimination of chronic viral infection by blocking CD27 signaling. J Exp Med 2006:203:2145-55
Crossref   Medline   1st Citation   2nd  

Mauri DN, Ebner, R, Montgomery, RA, Kochel, KD, Cheung, TC, Yu, GL. Light, a new member of the TNF superfamily, and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 1998:8:21-30
Crossref   Medline   1st Citation   2nd  

Maxwell JR, Weinberg, A, Prell, RA, Vella, AT. Danger and OX40 receptor signaling synergizes to enhance memory T cell survival by inhibiting peripheral deletion. J Immunol 2000:164:107-12
Medline   1st Citation  

McDonagh CF, Kim, KM, Turcott, E, Brown, LL, Westendorf, L, Feist, T. Engineered anti-CD70 antibody–drug conjugate with increased therapeutic index. Mol Cancer Ther 2008:7:2913-23
Crossref   Medline   1st Citation  

McHugh RS, Whitters, MJ, Piccrillo, CA, Young, DA, Shevach, EM, Collins, M. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002:16:311-23
Crossref   Medline   1st Citation   2nd  

Menoret A, Myers, LM, Lee, SJ, Mittler, RS, Rossi, RJ, Vella, AT. TGF beta protein processing and activity through TCR triggering of primary Cd8+ T regulatory cells. J Immunol 2006:177:6091-7
Medline   1st Citation  

Michel J, Langstein, J, Hofstadter, F, Schwarz, H. A soluble form of CD137 (ILA/4-1BB), a member of TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur J Immunol 1998:28:290-5
Crossref   Medline   1st Citation  

Montgomery RI, Warner, MS, Lum, BJ, Spear, PG. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 1996:87:427-36
Crossref   Medline   1st Citation  

Morel Y, Schiano de Colella, JM, Harrop, J, Deen, KC, Holmes, SD, Wattam, TA. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J Immunol 2000:2000:165:4397-404
1st Citation   2nd  

Morel Y, Truneh, A, Sweet, RW, Olive, D, Costello, RT. The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 2001:2001:167:2479-86
1st Citation  

Mueller DL, Jenkins, MK, Schwartz, RH. Clonal expansion versus clonal inactivation: a costimulatory signaling pathway determines the outcome of T antigen receptor occupancy. Annu Rev Immunol 1989:7:445-80
Medline   1st Citation  

Mungara AK, Brown, DL, Bishop, DK, Wood, SY, Cederna, PS. Anti-CD40L monoclonal antibody treatment induces long-term, tissue-specific, immunologic hyporesponsiveness to peripheral nerve allografts. J Reconstr Microsurg 2008:24:189-95
Crossref   Medline   1st Citation  

Munroe ME, Bishop, GA. A costimulatory function for T cell CD40. J Immunol 2007:171:671-82
1st Citation  

Muriglan SJ, Ramirez-Montagut, T, Alpdogan, O, Van Huystee, TW, Eng, JM, Hubbard, VM. GITR activation induces an opposite effect on alloreactive CD4(+) and CD8(+) T cells in graft-versus-host disease. J Exp Med 2004:200:149-57
Crossref   Medline   1st Citation  

Myers L, Croft, M, Kwon, BS, Mittler, RS, Vella, AT. Peptide-specific CD8 regulatory cells use IFN-g to elaborate TGF-β based suppression. J Immunol 2005:174:7625-32
Medline   1st Citation  

Nagumo H, Agematsu, K, Shinozaki, K, Hokibara, S, Ito, S, Takamoto, M. CD27/CD70 interaction augments IgE secretion by promoting the differentiation of memory B cells into plasma cells. J Immunol 1998:161:6496-502
Medline   1st Citation  

Nathan MJ, Yin, D, Eichwald, EJ, Bishop, DK. The immunobiology of inductive anti_CD40L therapy in transplantation: allograft acceptance is not dependent upon the deletion of graft-reactive T cells. Am J Transplant 2002:2:323-32
Crossref   Medline   1st Citation  

Niu L, Strahotin, S, Hewes, B, Zhang, B, Zhang, Y, Archer, D. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol 2007:178:4194-213
Medline   1st Citation  

Nocentini G, Riccardi, C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 2005:35:1016-22
Crossref   Medline   1st Citation   2nd  

Nocentini G, Giunchi, L, Ronchetti, S, Krausz, LT, Bartoli, A, Moraca, R. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci U S A 1997:94:6216-21
Crossref   Medline   1st Citation   2nd  

Nocentini G, Bartoli, A, Ronchetti, S, Giunchi, L, Cupelli, A, Delfino, D. Gene structure and chromosomal assignment of mouse GITR, a member of the tumor necrosis factor/nerve growth factor receptor family. DNA Cell Biol 2000:19:205-17
Crossref   Medline   1st Citation  

Nocentini G, Ronchetti, S, Bartoli, A, Spinicelli, S, Delfino, D, Brunetti, L. Identification of three novel mRNA splice variants of GITR. Cell Death Differ 2000:7:408-10
Crossref   Medline   1st Citation  

Ohshima Y, Tanaka, Y, Tozawa, H, Takahashi, Y, Maliszewski, C, Delespesse, G. Expression and function of Ox-40 ligand on human dendritic cells. J Immunol 1997:1997:189:3838-48
1st Citation  

Okumura M, Hidaka, Y, Kuroda, S, Takeoka, K, Tada, H, Amino, N. Increased serum concentration of soluble CD30 in patients with Grave's disease and Hashimotos's thyroiditis. J Clin Endocrinol Metabol 1997:82:1757-60
Crossref   1st Citation  

van Oers MH, Pals, ST, Evers, LM, van der Schoot, CE, Koopman, G, Bonfrer, JM. Expression and release of CD27 in human B-cell malignancies. Blood 1993:82:3430-6
Medline   1st Citation   2nd  

van Oosterwijk MF, Juwana, H, Arens, R, Tesselaar, K, van Oers, MH, Eldering, E. CD27–CD70 interactions sensitise naive CD4+ T cells for IL-12-induced Th1 cell development. Int Immunol 2007:19:713-8
Crossref   Medline   1st Citation  

Pan PY, Zang, Y, Weber, K, Meseck, ML, Chen, SH. Ox40 ligation enhances primary and cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther 2002:6:528-36
Crossref   Medline   1st Citation  

Paterson DJ, Jefferies, DJ, Green, JR, Brandon, MR, Corthesy, P, Puklavec, M. Antigens of activated rat T lymphocytes including a molecule of &007E;50,000 Mr detected only on CD4+ T blasts. Mol Immunol 1987:24:1281-90
Crossref   Medline   1st Citation  

Paulie S, Ehlin-Henriksson, B, Mellstedt, H, Koho, H, Ben-Aissa, H, Perlmann, P. A p50 surface antigen restricted to human urinary bladder carcinomas and B lymphocytes. Cancer Immunol Immunother 1985:20:23-8
Medline   1st Citation  

Pizzolo G, Vinante, F, Morosato, L, Nadali, G, Chilosi, M, Gandini, G. High serum level of the soluble form of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS. AIDS 1994:8:741-5
Medline   1st Citation  

Pizzolo F, Vinante, F, Nadali, G, Krampera, M, Morosato, L, Chilosi, M. High serum level of soluble CD30 in acute primary HIV-1 infection. Clin Exp Immunol 1997:108:251-3
Crossref   Medline   1st Citation  

Pollok KE, Kim, YJ, Zhou, Z, Hurtado, JC, Kim, KK, Pickard, RT. The inducible T cell antigen 4-1BB: analysis of expression and function. J Immunol 1993:150:771-81
Medline   1st Citation  

Quezada SA, Jarvinen, LZ, Lind, EF, Noelle, RJ. CD40/CD154 interaction at the interface of tolerance and immunity. Annu Rev Immunol 2004:22:307-28
Crossref   Medline   1st Citation  

Redmond WL, Weinberg, AD. Targeting OX40 and OX40L for the treatment of autoimmunity and cancer. Crit Rev Immunol 2007:27:415-36
Medline   1st Citation  

Ridge JP, Di Rosa, F, Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4− T-helper and a T-killer cell. Nature 1998:393:474-8
Crossref   Medline   1st Citation  

Rogers PR, Song, J, Gramaglia, I, Killeen, N, Croft, M. OX40 promotes Bcl-xL and Bcl-2 expression and essential for long-term survival of CD4+ T cells. Immunity 2001:164:445-55
1st Citation  

Romagnani S, Del Prete, G, Maggi, E, Chilosi, M, Caligaris-Cappio, F, Pizzolo, G. CD30 and type 2 T helper (Th2) responses. J Leukoc Biol 1995:57:726-30
Medline   1st Citation  

Romagnani P, Annunziato, F, Manetti, R, Mavilia, C, Lasagni, L, Manuelli, C. High CD30 ligand expression by epithelial cells and Hassal's corpuscles in the medulla of human thymus. Blood 1998 May 1:91:9:3323-32
Medline   1st Citation  

Ronchetti S, Nocentini, G, Riccardi, C, Pandolfi, PP. Role of GITR in activation response of T lymphocytes. Blood 2002:100:350-2
Crossref   Medline   1st Citation  

Rooney IA, Butrovich, KD, Glass, AA, Borborodu, S, Bendict, CA, Whitbeck, JC. The lymphotoxin β receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem 2000:275:14307-15
Crossref   Medline   1st Citation  

Salek-Ardakani S, Croft, M. Regulation of CD4 T cell memory by OX40 (CD134). Vaccine 2006:13:872-83
1st Citation  

Schauer SL, Wang, Z, Sonenshein, GE, Rothstein, TL. Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40 ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through modulation of I kappa B proteins. J Immunol 1996:157:81-6
Medline   1st Citation  

Scheu S, Alferink, J, Pötzel, T, Barchet, W, Kalinke, U, Pfeffer, K. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. J Exp Med 2002:195:1613-24
Crossref   Medline   1st Citation  

Schnell R, Staak, O, Borchmann, P, Schwartz, C, Matthey, B, Hansen, H. A phase I study with an anti-CD30 ricin A-chain immunotoxin (ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma. Clin Cancer Res 2002:8:1779-86
Medline   1st Citation  

Schonbeck U, Libby, P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 2001:58:4-43
Crossref   Medline   1st Citation  

Schuurhuis DH, Laban, S, Toes, RE, Ricciardi-Castagnoli, P, Kleijmeer, MJ, van der Voort, EI. Immature dendritic cells acquire CD8+ cytotoxic T lymphocyte priming capacity upon activation by T helper cell-independent or-dependent stimuli. J Exp Med 2000:192:145-50
Crossref   Medline   1st Citation  

Schwab U, Stein, H, Gerdes, J, Lemke, H, Kirchner, H, Schaadt, M. Production of a monoclonal antibody specific for Hodgkin and Sternberg±Reed cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature 1982:299:65-7
Crossref   Medline   1st Citation  

Seo SK, Choi, JH, Kim, YH, Kang, WJ, Park, HY, Suh, JH. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat Med 2004:10:1088-94
Crossref   Medline   1st Citation   2nd  

Shaikh RB, Santee, S, Granger, SW, Buitrovich, K, Cheung, T, Kronenberg, M. Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J Immunol 2000:167:6330-7
1st Citation  

Shimizu J, Yamazaki, S, Takahashi, T, Ishida, Y, Sakaguchi, S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self tolerance. Nat Immunol 2002:3:135-42
Crossref   Medline   1st Citation   2nd  

Shin HH, Lee, MH, Kim, SG, Lee, YH, Kwon, BS, Choi, HS. Recombinant glucocorticoid induced tumor necrosis factor receptor (rGITR) induces NOS in murine macrophage. FEBS Lett 2000:514:275-80
Crossref   1st Citation  

Shin HH, Kwon, BS, Choi, HS. Recombinant glucocorticoid induced tumour necrosis factor receptor (rGITR) induced COX-2 activity in murine macrophage Raw 264.7 cells. Cytokine 2002:19:187-92
Crossref   Medline   1st Citation  

Shin HH, Lee, HW, Choi, HS. Induction of nitric oxide synthase (NOS) by soluble glucocorticoid induced tumor necrosis factor receptor (sGITR) is modulated by IFN-gamma in murine macrophage. Exp Mol Med 2003:35:175-80
Medline   1st Citation  

Smith CA, Gruss, HJ, Davis, T, Anderson, D, Farrah, T, Baker, E. CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell 1993:73:1349-60
Crossref   Medline   1st Citation  

So T, Croft, M. Cutting edge: OX40 inhibits TGF-beta- and antigen-driven conversion of naive CD4 T cells into CD25+ Foxp3+ T cells. J Immunol 2007:179:1427-30
Medline   1st Citation  

So T, Lee, SW, Croft, M. Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine Growth Factor Rev 2008:19:253-62
Crossref   Medline   1st Citation  

Stamenkovic I, Clark, EA, Seed, B. A B lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J 1989:8:1403-10
Medline   1st Citation  

Stuber E, Strober, W. The T cell–B cell interactions via OX40/OX40L is necessary for the T cell-dependent humoral immune response. J Exp Med 1996:183:979-89
Crossref   Medline   1st Citation  

Stuber E, Neurath, M, Calderhead, D, Fell, HP, Strober, W. Cross-linking of Ox-40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity 1995:2:507-21
Crossref   Medline   1st Citation  

Sugumura K, Ishii, N, Wienberg, AD. The therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol 2004:4:420-31
Crossref   Medline   1st Citation  

Sun Y, Chen, HM, Subudhi, SK, Chen, J, Koka, R, Chen, L. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 2002:8:1405-13
Crossref   Medline   1st Citation  

Suri A, Shimizu, J, Katz, JD, Sakaguchi, S, Unanue, ER, Kanagawa, O. Regulation of autoimmune diabetes by non-islet-specific Tcells – a role for the glucocorticoid-induced TNF receptor. Eur J Immunol 2004:34:447-54
Crossref   Medline   1st Citation  

Tamada K, Shimozaki, K, Chapoval, AI, Zhai, Y, Su, J, Chen, SF. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J Immunol 2000:164:4105-10
Medline   1st Citation   2nd   3rd  

Tamada K, Shimozaki, K, Chapoval, AI, Zhu, G, Sica, G, Flies, D. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat Med 2000:6:283-9
Crossref   Medline   1st Citation   2nd   3rd  

Tamada K, Tamura, H, Flies, D, Fu, YX, Celis, E, Pease, LR. Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J Clin Invest 2002:2002:109:549-57
1st Citation  

Telford WG, Nam, SY, Podack, ER, Miller, RA. CD30-regulated apoptosis in murine CD8 T cells after cessation of TCR signals. Cell Immunol 1997:182:125-36
Crossref   Medline   1st Citation   2nd  

Tesselaar K, Arens, R, van Schijndel, GM, Baars, PA, van der Valk, MA, Borst, J. Lethal T cell immunodeficiency induced by chronic costimulation via CD27–CD70 interactions. Nat Immunol 2003:4:49-54
Crossref   Medline   1st Citation  

Toes RE, Schoenberger, SP, van der Voort, EI, Offringa, R, Melief, CJ. CD40-CD40Ligand interactions and their role in cytotoxic T lymphocyte priming and anti-tumor immunity. Semin Immunol 1998:10:443-8
Crossref   Medline   1st Citation  

Toubi E, Shoenfeld, Y. The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 2004:37:457-64
Crossref   Medline   1st Citation  

Uraushihara K, Kanai, T, Ko, K, Totsuka, T, Makita, S, Iiyama, R. Regulation of murine inflammatory bowel disease by CD25+ and CD25− CD4+ glucocorticoid-induced TNF receptor family-related gene+regulatory T cells. J Immunol 2003:171:708-16
Medline   1st Citation  

Vinay DS, Kwon, BS. Genes, transcripts, and proteins of CD137 receptor and ligand. CD137 pathway: immunology and diseases 2006:1-14
1st Citation  

Vinay DS, Cha, K, Kwon, BS. Dual immunoregulatory pathways of 4-1BB signaling. J Mol Med 2006:84:726-36
Crossref   Medline   1st Citation   2nd  

Vinay DS, Kim, JD, Kwon, BS. Amelioration of mercury-induced autoimmunity by 4-1BB. J Immunol 2006:177:5708-17
Medline   1st Citation   2nd  

Wang J, Lo, JC, Foster, A, Yu, P, Chen, HM, Wang, Y. The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J Clin Invest 2001:108:1771-80
Medline   1st Citation  

Wang Y, Subudhi, SK, Anders, RA, Lo, J, Sun, Y, Blink, S. The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. J Clin Invest 2004:113:826-35
Medline   1st Citation  

Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 2005:23:23-68
Crossref   Medline   1st Citation   2nd  

Weinberg AD. Antibodies to Ox-40 (CD134) can identify and eliminate autoreactive T cells: implications for human auto-immune disease. Mol Med Today 1998:4:76-83
Crossref   Medline   1st Citation  

Weinberg AD. OX40: targeted immunotherapy implications for tempering autoimmunity and enhancing vaccines. Trends Immunol 2002:23:102-9
Crossref   Medline   1st Citation  

Weinberg AD, Bourdette, DN, Sullivan, TJ, Lemon, M, Wallin, JJ, Maziarz, R. Selective depletion of myelin-reactive T cells with the anti-OX-40 antibody ameliorates autoimmune encephalomyelitis. Nat Med 1996:2:183-9
Crossref   Medline   1st Citation  

Weinberg AD, Wegmann, KW, Funutake, C, Whitham, RH. Blocking Ox-40/Ox-40 ligand interaction in vitro and in vivo leads to decreased T-cell function and amelioration of EAE. J Immunol 1999:162:1818-26
Medline   1st Citation   2nd  

Weinberg AD, Rivera, MM, Prell, R, Morris, A, Ramstad, T, Vetto, JT. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 2000:164:2160-9
Medline   1st Citation  

Weinberg AD, Evans, DE, Thahofer, C, Shi, T, Prell, RA. The generation of T cell memory: a review describing the molecular and cellular events following OX40 (CD134) engagement. J Leukoc Biol 2004:75:962-72
Crossref   Medline   1st Citation   2nd  

Wilcox RA, Chapoval, AI, Gorski, KS, Otsuji, M, Shin, T, Flies, DB. Cutting edge: expression of functional CD137 receptor by dendritic cells. J Immunol 2002:168:4262-7
Medline   1st Citation  

Xiao Y, Hendriks, J, Langerak, P, Jacobs, H, Borst, J. CD27 is acquired by primed B cells at the centroblast stage and promotes germinal center formation. J Immunol 2004:172:7432-41
Medline   1st Citation  

Yamada A, Salama, AD, Sho, M, Najafian, N, Ito, T, Forman, JP. CD70 signaling is critical for CD28-independent CD8β T cell-mediated alloimmune responses in vivo. J Immunol 2005:174:1357-64
Medline   1st Citation  

Zhai Y, Guo, R, Hsu, TL, Yu, GL, Ni, J, Kwon, BS. LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J Clin Invest 1998:102:1142-51
Crossref   Medline   1st Citation  


Received 2 December 2008; accepted 4 February 2009

doi:10.1016/j.cellbi.2009.02.001


ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
Published by Portland Press Limited on behalf of the International Federation for Cell Biology (IFCB)