A New Class of Reverse Signaling Costimulators Belongs to the TNF Family Mingyi Sun and Pamela J. Fink This information is current as J Immunol 2007; 179:4307-4312; ; of September 27, 2021. doi: 10.4049/jimmunol.179.7.4307 http://www.jimmunol.org/content/179/7/4307

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JOURNAL OF IMMUNOLOGY

BRIEF REVIEWS

A New Class of Reverse Signaling Costimulators Belongs to the TNF Family Mingyi Sun and Pamela J. Fink1

Recent evidence shows that many molecules of the TNF still remains unclear (7). The N-terminal cytoplasmic domains family serve as counter-receptors, inducing costimulation of most TNF family members are conserved across species but through reverse signals in addition to delivering signals not between family members, suggesting that the intracellular through their respective TNF receptors. In this review, we domains of TNF family members play a key role in their bio- will discuss this new class of costimulators with a focus on logical functions. Of interest in the search of a focal point for reverse signaling induced by these members, six (CD70, Fas li- the mechanism of costimulation transduced by reverse sig- ␣ naling through Fas . The Journal of Immunology, gand (FasL), CD30L, CD40L, 4-1BBL, and TNF- )of10 Downloaded from 2007, 179: 4307–4312. molecules with bidirectional capacity contain at least one puta- tive casein kinase I (CKI) binding site, suggesting that reverse he TNF family thus far includes 19 identified mem- signaling may depend on this motif (8, 9). bers, all of which, with the exception of the secreted T (LT)2 ␣ and a proliferation-inducing li- CD40L (CD154) gand (APRIL), are type II transmembrane containing a Although CD40 signaling initiated by the interaction of http://www.jimmunol.org/ ϩ C-terminal TNF homology domain that binds to cysteine re- CD40-bearing APC and CD40L-bearing CD4 T cells is es- peat domains of one or more molecules belonging to the TNF sential for APC activation and humoral immune responses, receptor (TNFR) family (1). Although TNFR family members CD40L has been recognized for more than a decade to costimu- are expressed by a wide variety of cells, almost all of the TNF late via CD40L-mediated reverse signaling (10). Evidence sug- ϩ proteins are expressed by cells of the , including gests that CD40L is preformed and stored in naive CD4 T B cells, T cells, NK cells, dendritic cells (DCs), and monocytes cells (11). Its expression is rapidly but transiently induced on T (2). TNF-TNFR interactions initiate multiple signaling path- cells upon activation through the TCR, but concomitant CD28

ways promoting cell survival, death, differentiation, or inflam- signaling is required for prolonged high-level CD40L expres- by guest on September 27, 2021 mation in TNFR-expressing cells, depending on the activation sion (12–14). CD40L costimulation is critical for the develop- ϩ state of the cells and the expression levels of the TNFR family ment of CD4 -dependent effector functions (15–17), molecules. because mice lacking CD40L-transduced costimulation due to Although many TNF family proteins can be expressed in sol- CD40 deficiency are unable to make Ab responses or generate uble form or released from the cell surface following cleavage by germinal centers. The administration of soluble CD40 to specific proteases (2, 3), most act as membrane-bound factors CD40 knockout mice restores the missing signal delivered and require direct cell-to-cell contact. The possibility therefore through CD40L (18). However, the requirement of CD40L- ϩ exists for the bidirectional transfer of information upon TNF- mediated costimulation for CD8 T cell responses is unclear, as TNFR ligation. Indeed, data from many groups published over experiments have blocked the delivery of both forward signals the past 17 years are consistent with the notion that many mol- through CD40 and reverse signals through CD40L (19, 20). ecules of the TNF family receive as well as deliver signals The observed close homology between human and mouse through their respective receptors (Fig. 1). In this review, we use CD40L cytoplasmic tails implies the functional importance of the term “reverse signal” to designate the signal delivered this domain. The molecular mechanism of CD40L costimula- through the TNF family member and the term “counter-recep- tion remains uncertain, given that CD40L has a very short cy- tors” to denote the TNF family members that play such a dou- toplasmic tail of only 22 aa, lacking any known enzymatic ac- ble role (4–6). The reverse signals we describe in this review are tivity. There is evidence indicating that the activation of T cells those that deliver costimulatory signals, thereby altering the dif- via CD40L stimulation alone induces tyrosine phosphorylation ferentiation state or function of the TNF-expressing cells (Ta- of cellular proteins including Lck and phospholipase C␥ ble I). How TNF family members balance these multiple tasks (PLC␥), which further activates kinase C (PKC).

Department of Immunology, University of Washington, Seattle, WA 98195 2 Abbreviations used in this paper: LT, lymphotoxin; CKI, casein kinase I; DC, ; FasL, ; HVEM, herpes simples virus entry mediator; LIGHT, homologous Received for publication June 13, 2007. Accepted for publication August 14, 2007. to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for The costs of publication of this article were defrayed in part by the payment of page charges. HVEM, a receptor expressed on T cells; mTNF, membrane-bound TNF␣; RANK, recep- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. tor activator of NF␬B; SH3, Src homology 3; TNFR, TNF receptor; TRANCE, TNF- Section 1734 solely to indicate this fact. related activation-induced . 1 Address correspondence and reprint requests to Dr. Pamela J. Fink, Department of Im- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 munology, University of Washington, I-607H Health Sciences Center, Campus Box 357650, Seattle, WA, 98195. E-mail address: [email protected]

www.jimmunol.org 4308 BRIEF REVIEWS: TNF MOLECULE-MEDIATED COSTIMULATION VIA REVERSE SIGNALING

ment of human autoimmune diseases such as systemic ery- thematosus (36).

TRANCE TRANCE (TNF-related activation-induced cytokine), also known as receptor activator of NF-␬B (RANK) ligand or osteo- protegrin ligand, can be induced on activated T cells, particularly ϩ CD4 Th1 cells, and secreted by /stromal cells (37, 38). TRANCE surface expression can be further enhanced by CD28 FIGURE 1. TNF family members can generate bidirectional signals. TNF- TNFR ligation generates bidirectional signals. TNF family members induce costimulation (39). TRANCE is not only a regulator of the im- forward signals delivered through their respective receptors that promote cell mune system and osteoclastogenesis via interaction with RANK survival, death, differentiation, or in cells expressing members of and osteoprotegrin (39–41), it also mediates p38 MAPK-depen- the TNFR family, depending on the activation state of the cells and the expres- dent reverse signaling and costimulates Th1 cells to enhance IFN-␥ sion levels of the TNFR family molecules. In addition, TNFR family members secretion by co-cross-linking TCR and TRANCE with immobi- also serve as ligands to initiate reverse signaling, regulating cell proliferation, lized anti-TCR␤ and a RANK-Fc fusion protein (42). In addition cytokine secretion, oxidative burst, class switch, and T cell maturation in cells to its role in T cell costimulation, recent studies show that reverse expressing molecules belonging to the TNF family. signaling through TRANCE also occurs in chronic lympho- cytic leukemia to induce IL-8 production, contributing to the Downloaded from pathogenesis of these cells (43). CD40L cross-linking by anti-CD40L also triggers JNK and p38 activation (21, 22). These data suggest that CD40L also 4-1BBL functions as a direct stimulatory molecule for T cells despite its short cytoplasmic tail. Although studies of 4-1BB/4-1BBL interactions have been

mainly focused on 4-1BB-mediated costimulation in T cells, it http://www.jimmunol.org/ LIGHT has become clear that 4-1BBL can signal in both directions LIGHT (homologous to lymphotoxin, exhibits inducible ex- (44). 4-1BBL is constitutively expressed on , pression and competes with herpes simplex virus glycoprotein monocytes, DCs, and B cells; it can also be induced on activated D for herpes simplex virus entry mediator (HVEM), a receptor T cells (45, 46). Reverse signaling has been demonstrated for 4- expressed on T cells; designation is derived from underlined let- 1BBL (47); cross-linking 4-1BBL by using immobilized 4-1BB ters) binds to HVEM, a costimulatory receptor belonging to the costimulates B cell proliferation and Ig production (48). TNFR family, the LT␣␤ receptor, and TR6/DcR3, a soluble 4-1BBL is also a monocyte activation factor, because cross-link- ing 4-1BBL on monocytes by immobilized 4-1BB induces ex- TNFR family member that also binds to FasL and TL1A (23, ␣ by guest on September 27, 2021 24). Induced on activated T cells and immature DCs, LIGHT pression of IL-6, IL-8, and TNF- and inhibits expression of has multiple functions (23, 25). LIGHT can induce IL-10 (49). Furthermore, 4-1BBL reverse signaling enhances in cells expressing HVEM and LT␤R (26) and can also act as a the migration and infiltration of monocytes in vitro and in vivo receptor to costimulate T cell proliferation, CTL activity, and (50). It has recently been shown that 4-1BBL can also act as a cytokine production upon ligation by engineered, solid phase coreceptor for TLRs to enhance TNF production in macro- TR6/DcR3 or anti-LIGHT (27–29). Because FasL also inter- phages (51). In this case, 4-1BBL-mediated reverse signaling is acts with TR6/DcR3, it is possible that this TR6/DcR3-in- not initiated by ligand binding and cannot be defined as co- duced T cell costimulation operates through FasL-mediated re- stimulation because it does not boost TCR signaling. The un- verse signaling (see below). Although HVEM can also deliver derlying mechanism of 4-1BBL reverse signaling is unknown. reverse signals through the Ig superfamily member B and T ␣ lymphocyte attenuator to negatively regulate T cell responses Membrane-bound TNF- (mTNF) (30), it is unknown whether this interaction influences Since the identification of the soluble form of TNF-␣ Ͼ30 LIGHT-mediated reverse signaling. The molecular basis of years ago, this molecule has been recognized as a pleiotropic cy- LIGHT-mediated costimulation is still unclear, although re- tokine. It is mainly produced by macrophages but also by a cent studies show that LIGHT and TCR co-cross-linking en- broad variety of other cells and tissues, including lymphoid hances Erk1/2 activation (27). cells, mast cells, endothelial cells, fibroblasts, and neuronal tis- sue. Membrane-integrated and soluble TNF-␣ bind to two re- TRAIL ceptors, TNFR1 and TNFR2, and induce multiple signals (52). Although TRAIL is another death-inducing TNF family member TNF-␣ induces cell death in certain circumstances through a (31), it also has the capacity to costimulate T cells. It is expressed in TNFR1-mediated, death domain and caspase-dependent path- a variety of cell types and can be up-regulated on activated NK cells way, although in most scenarios TNF-TNFR1 ligation induces and T cells (32–34). In conjunction with suboptimal anti-CD3, inflammatory responses by NF-␬B activation via TNFR-asso- cross-linking TRAIL by a plate-bound TRAIL receptor 1-Fc fu- ciated factor 2 (TRAF2). In contrast, TNFR2 mainly mediates ϩ sion protein can selectively enhance CD4 T cell proliferation and nonapoptotic signaling upon binding to TNF-␣. For example, ϩ IFN-␥ production (35, 36). Moreover, the IFN-␥ augmentation TNFR2 is a costimulator for CD8 T cells (53). mTNF can can be reversed by a p38 MAPK inhibitor, suggesting that p38 also deliver reverse signals initiated by anti-TNF mediated MAPK is involved in TRAIL-mediated costimulation. Some stud- cross-linking, which costimulate T cells to express ies also suggest that enhanced reactivity of T cells to autoantigens as and adhesion molecules (54–56). Reverse signaling by mTNF ϩ ϩ a result of TRAIL costimulation may play a role in the develop- differentially regulates CD4 and CD8 T cell activity against The Journal of Immunology 4309

Table I. TNF family members that transduce reverse signals

Counter- Receptor Expression Receptor Expression Readouts of Reverse Signaling References

CD40L Activated T cells CD40 B cells, DCs Costimulation, direct stimulation 10–22

LIGHT Activated T cells, HVEM T, B, NK cells, DCs, Costimulation 23–30 immature DCs, myeloid cells monocytes TR6/DcR3 , , colon cells

TRANCE Activated T cells RANK Most cell types Costimulation 37–43

TRAIL Activated NK cells, T TRAILR1 Most cell types Costimulation 31–36 cells

CD30L , B cells, CD30 Resting CD8 T cells, Costimulation, direct stimulation, inhibition 61–64 macrophages, activated T and B cells neoplastic cells, activated T cells

FasL Activated NK cells, T Fas Most cell types Costimulation 65–83 Downloaded from cells TR6/DcR3 Lung, stomach, colon cells

mTNF Macrophages, TNFR2 Immune cells, endothelial Costimulation, desensitization 52–60 monocytes cells

4-1BBL Activated T cells, B 4-1BB Activated T cells, B cells, Costimulation of B cells, activation, 44–51 http://www.jimmunol.org/ cells, DCs, activated DCs migration, and infiltration of monocytes activated monocytes

OX40L Activated T cells, B OX40 Activated T cells, B cells, Direct stimulation 4, 5 cells, DCs, activated DCs activated monocytes

CD70 Activated T cells, B CD27 T cells, activated B cells Direct stimulation 6 cells, DCs, by guest on September 27, 2021 activated monocytes allogeneic endothelial cells by attenuating the proliferative po- proliferation, IL-8 production, and oxidative burst (62). In ad- ϩ tential of Th2 cells and increasing the cytotoxicity of CD8 T dition, viral CD30, a soluble CD30 homologue encoded by the cells (57). Surprisingly, reverse signaling initiated by engaging ectromelia virus, binds to CD30L and transduces a negative re- mTNF with soluble TNFRs also leads to the desensitization of verse signal by blocking Th1 but not Th2 cytokine-mediated T monocytes and macrophages to LPS by down-regulating the cell responses to viral infection (63). Furthermore, CD30L ex- production of soluble TNF, IL-6, IL-1, and IL-10 (58, 59). It is pressed on B cells can also mediate a negative reverse signal to unclear how these soluble TNFRs cross-link mTNF to induce inhibit class switch recombination as well as Ig production (64). reverse signals instead of inhibiting this interaction. It is possi- However, these experiments are not entirely clear, as forward ble that soluble TNFRs transiently interact with proteins on the signals through CD30 could also be blocked (63). The mecha- cell surface or the extracellular matrix to form oligomeric struc- nism of CD30L-mediated reverse signaling is still unknown. tures. These data suggest that soluble TNFR shed during in- flammation might have the potential to bind mTNF and thereby down-regulate inflammation. Although more evidence FasL (CD178) is needed to identify the molecular mechanism of mTNF-me- FasL has been well characterized for its induction of cell death diated costimulation, CKI is likely involved in the signaling through the (65). Its expression is mainly induced pathway because it phosphorylates serine residue 5 of the on hemopoietic cells such as activated T cells and NK cells. mTNF cytoplasmic domain upon cell activation in vitro (60). However, some nonhemopoietic cells involved in immune privilege and tumor escape also express FasL (66). A naturally CD30L (CD153) arising point mutation in the FasL in gld mice results in the CD30L was first found on activated peripheral blood T cells expression of nonfunctional FasL that can no longer bind Fas (61) but is also constitutively expressed on neutrophils, B cells, (67). Exploration of the reverse signaling capacity of FasL has macrophages, and neoplastic cells (61, 62). CD30-CD30L in- provided both in vivo and in vitro evidence that this molecule teractions generate bidirectional signals; CD30L cross-linking costimulates thymocyte maturation (68) and mature T cell pro- ϩ ϩ by anti-CD30L costimulates T cells to induce proliferation and liferation with a stronger influence on CD8 than on CD4 T ϩ ϩ cytokine production and stimulates neutrophils to enhance cell cells (69–71). The differential sensitivity of CD4 and CD8 4310 BRIEF REVIEWS: TNF MOLECULE-MEDIATED COSTIMULATION VIA REVERSE SIGNALING

FIGURE 2. Distinct motifs within the cytoplasmic domain of FasL regulate costimulation. Diagrammed is a summary of the motifs identified within the cytoplas- mic domain of FasL involved in downstream signaling events. Both FasL and Fas are localized in lipid rafts (la- beled in green). Amino acids 45–54 (especially aa 45– 50) in the proline-rich region (labeled in orange) regu- late cell proliferation and cytokine production through PI3K and MAPK pathways, whereas the two CKI bind- ing sites (labeled in red) are involved in NFAT activa- tion via an unknown pathway.

T cells to FasL costimulation and Fas-mediated death, in con- stimulation in vivo in the absence of lymphoproliferative dis- junction with the kinetics of FasL expression for the two T cell ease. In addition, serine/threonine residues in the CKI binding Downloaded from subpopulations, may regulate the timing of these two possible sites of the FasL tail are essential for FasL costimulation-medi- outcomes: costimulation vs death (70). Furthermore, costimu- ated NFAT activation, and at least one of the CKI binding sites lation mediated by FasL requires TCR coengagement and is in- is phosphorylated by recombinant CKI in vitro (86). These re- dependent of costimulation through CD28 (72). sults suggest that CKI is responsible for phosphorylating FasL at The FasL cytoplasmic domain is the longest of the 19 known serine/threonine residues to induce downstream signaling, al- TNF family members (1). Despite little cross-family sequence though the upstream pathway triggering NFAT activation and http://www.jimmunol.org/ homology, the cytoplasmic domain of FasL is nearly as con- the readout of this NFAT activation upon FasL costimulation served across species as is the Fas binding extracellular domain are still not well defined (Fig. 2). It is possible that the phos- (73). The FasL cytoplasmic domain does not contain any phorylation status of these serine/threonine residues is impor- ITAM-, ITIM-, YXXM- (the tyrosine phosphorylation motif tant for regulating the function of glycogen synthase kinase 3 shared with Ig superfamily members), or TNFR-associated fac- (GSK3), a molecule involved in the PI3K pathway and known tor (TRAF)-interacting motifs and, hence, is likely to transduce to promote the nuclear export of NFAT (81). Recently, it has signals distinct from those delivered by the TCR and costimu- been shown that two proteases can collaborate to cleave human lators of the CD28 or TNFR family. Although there is only a FasL overexpressed in T cells and release a smaller and highly by guest on September 27, 2021 single tyrosine residue in the murine FasL cytoplasmic tail, there are three threonine and eight serine residues and two po- tential CKI binding sites (S/TXXS/T). Also of interest, the FasL tail contains a striking proline-rich region not found in any other TNF family member (Fig. 2). This region includes several consensus Src homology 3 (SH3) and WW binding domains, and FasL peptides spanning this region can associate in vitro with many SH3-containing proteins, including Fyn, Grb2, and PI3K (74–77). In hemopoietic cells, FasL is retained within se- cretory vesicles to be transported to the cell surface upon acti- vation, and the proline-rich region in the FasL cytoplasmic tail is responsible for protein transport from the Golgi to secretory vesicles (78, 79). The molecular mechanism of FasL costimulation has been explored recently (72). The proline-rich intracellular domain of ϩ FasL is sufficient to costimulate CD8 T cells by recruiting FasL into lipid rafts, associating with select SH3-containing proteins, further enhancing the phosphorylation of Akt, Erk1/2, JNK, and FasL itself, activating the transcription fac- tors NFAT and AP-1, and enhancing cytokine production and FIGURE 3. Summary of the pathway of signal transduction mediated by cell proliferation (Fig. 3). Mutagenesis studies have shown that FasL costimulation. Diagrammed is a schematic summary of the signaling residues 45–54 in the proline-rich region are critical for FasL- events driving transcription factor activation initiated upon TCR cross-linking mediated costimulation requiring both the PI3K and MAPK and FasL costimulation. FasL is localized in lipid rafts (labeled in green) upon pathways (Fig. 2), although FasL molecules lacking aa 45–54 FasL costimulation. The arrows between the protein components reflect either show normal surface expression and killing through Fas (86). direct interactions or enzymatic activity of one protein directed against another. The readouts of the signaling pathways are cytokine production and cell pro- Because both the gld and the FasL knockout mice used for in- liferation (in pink). Proteins identified to associate physically with FasL are vestigating FasL costimulation in vivo have a very strong pa- marked in orange. Proteins that can be phosphorylated upon FasL costimula- thology (67, 80), this deletional mutation should be a useful tion are marked in red. Rectangles mark the transcription factors (in dark blue) candidate for generating a knock-in mouse to study FasL co- translocated to the nucleus upon FasL costimulation. The Journal of Immunology 4311 unstable fragment consisting mainly of the FasL intracellular 11. Casamayor-Palleja, M., M. Khan, and I. C. MacLennan. 1995. A subset of CD4ϩ memory T cells contains preformed CD40 ligand that is rapidly but transiently ex- domain. This small fragment can enter the nucleus, perhaps pressed on their surface after activation through the T cell receptor complex. J. Exp. providing an alternate mechanism for reverse signaling through Med. 181: 1293–1301. 12. Roy, M., T. Waldschmidt, A. Aruffo, J. A. Ledbetter, and R. J. Noelle. 1993. 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