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 References This article cites 85 articles, 38 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/179/7/4307.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on September 27, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE 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 ligand. 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 lymphotoxin (LT)2 ␣ and a proliferation-inducing li- CD40L (CD154) gand (APRIL), are type II transmembrane proteins 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 immune system, 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 T cell-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 protein 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, dendritic cell; FasL, Fas ligand; 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 cytokine. 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 lupus 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 osteoblasts/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 inflammation 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 B cell 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 macrophages, pression and competes