Robust B Cell Immunity but Impaired T Cell Proliferation in the Absence of CD134 (OX40) Susanne D. Pippig, Claudia Peña-Rossi, James Long, Wayne R. Godfrey, Deborah J. Fowell, Steven L. Reiner, Marian L. This information is current as Birkeland, Richard M. Locksley, A. Neil Barclay and Nigel of September 26, 2021. Killeen J Immunol 1999; 163:6520-6529; ; http://www.jimmunol.org/content/163/12/6520 Downloaded from References This article cites 66 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/163/12/6520.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: 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 © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Robust B Cell Immunity but Impaired T Cell Proliferation in the Absence of CD134 (OX40)1 Susanne D. Pippig,2,3* Claudia Pen˜a-Rossi,2,4* James Long,* Wayne R. Godfrey,* Deborah J. Fowell,† Steven L. Reiner,‡ Marian L. Birkeland,§ Richard M. Locksley,*†¶ A. Neil Barclay,§ and Nigel Killeen5* CD134 (OX40) is a member of the TNF receptor family that is expressed on activated T lymphocytes. T cells from mice that lack expression of CD134 made strong responses to a range of challenges, but they showed impaired proliferation in response to direct stimulation through the TCR with monoclonal anti-CD3e Ab. CD134-deficient mice controlled infection with Leishmania major, Nippostrongylus brasiliensis, and Theiler’s murine encephalomyelitis virus, and they made overtly normal Ab responses to a variety of antigens. Thus, CD134 is not essential for many T cell responses in vivo, nor is it required for the provision of help to B cells. Nonetheless, a subtle role in the regulation of T cell reactivity is suggested by the effect of CD134 deficiency on in vitro T Downloaded from cell responses. The Journal of Immunology, 1999, 163: 6520–6529. embers of the TNF receptor superfamily have promi- apoptotic or proliferative/differentiative outcomes through the re- nent roles in the regulation of immune responses and spective activation of caspases and transcriptional regulators such the formation of secondary lymphoid tissue (1–7). Li- as NF-kB and AP-1 (7, 12). Mutant mice that lack expression of M http://www.jimmunol.org/ gands for these receptors also constitute a superfamily whose TNF receptors, their ligands, or TRAFs show a range of defects in members share structural similarity to TNF and in many cases are lymphoid homeostasis and immune responses (3, 5, 6, 13–16). likely to form cell-bound or secreted trimers (8, 9). Lymphocyte The CD134 Ag was first identified as a 50-kDa glycoprotein activation induces the expression of several TNF receptor-related target for the MRC OX40 Ab that was selectively expressed on proteins or their ligands including CD40L, CD95L, 4-1BB, CD30, activated rat CD41 T cells (17). Mouse and human CD134 show and CD134 (10). This up-regulation of expression allows for li- a similar pattern of expression to the rat form, except they are also gand-dependent signals to be relayed from the receptors to the found on activated CD81 T cells (18, 19). The ligand for CD134 nucleus through signaling molecules that include the TNF recep- (CD134L) is a type II trimeric transmembrane protein whose tor-associated factors (TRAFs)6 (4, 11, 12). These signals induce mRNA is markedly induced in human T cell leukemia virus 1-in- by guest on September 26, 2021 fected cells through the action of the viral tax transactivator (19, 20). Trimeric CD134L binds to cell surface CD134 with high affinity (Kd 2 2 † ¶ 5 5 3 5 1 Departments of *Microbiology and Immunology and Medicine, and Howard 0.2–0.4 nM) and a slow off-rate (koff 4 10 s ) (8). ‡ Hughes Medical Institute, University of California, San Francisco, CA 94143; De- In several experimental settings, CD134 acts as a costimulator partment of Medicine, Committee on Immunology and the Gwenn Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637; and for T cells. For instance, anti-CD134 mAb augments the response §Medical Research Council Cellular Immunology Unit, Sir William Dunn School of of rat T cells activated with allogenic MHC (17) or anti-CD3 (21). Pathology, University of Oxford, Oxford, United Kingdom Similarly, mouse and human T cells make more robust prolifera- Received for publication July 20, 1999. Accepted for publication October 7, 1999. tive and cytokine responses when activated in the presence of The costs of publication of this article were defrayed in part by the payment of page transfected cells expressing CD134L (19, 20, 22). This costimu- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. latory activity appears to be synergistic with costimulation through 1 This work was supported by a grant-in-aid (to N.K.) from the American Heart CD28 and is particularly potent in prolonging the responses of Association (96-221) and by funds from the Lucille P. Markey Foundation through differentiated effector T cells (23). Interestingly, a similar type of the University of California, San Francisco, Program in Biological Sciences and the Howard Hughes Medical Institute University of California, San Francisco, Research costimulatory activity has also been described for CD137 (4-1BB), Resources Program. S.D.P., C.P-R., D.J.F., and M.L.B. were supported by postdoc- which is a related member of the TNF receptor family that is also toral fellowships from the Deutsche Forschungsgemeinschaft, the Human Frontiers in induced on activated T lymphocytes (24–26). Costimulatory sig- Science Program, the Juvenile Diabetes Foundation, and the Cancer Research Insti- tute (NY), respectively. W.R.G. was the recipient of a U.S. Public Health Service nals delivered through CD134 have been implicated in selectively Career Development Award. R.M.L. is an Investigator in the Howard Hughes Med- promoting the differentiation of Th2 cells (27–29), but other stud- ical Institute. A.N.B. was supported by the Medical Research Council (U.K.). ies suggest they may also regulate Th1 development (23, 30, 31). 2 S.D.P. and C.P-R. contributed equally to this work. The cytoplasmic tail of CD134 can associate with TRAF2, 3 Current address: Systemix Inc., Palo Alto, CA. TRAF3, and TRAF5 and may well mediate its costimulatory effect 4 Current address: Ares-Serono International S.A., 14, Chemin des Aulx, 1228 Plan- through these interactions (12, 32, 33). Finally, recent data indicate les Ouates, Switzerland. that like anti-CD137 (34), anti-CD134 signaling can block activa- 5 Address correspondence and reprint requests to Dr. Nigel Killeen, Department of Microbiology and Immunology, University of California, San Francisco, CA 94143- tion-induced T cell death in mice treated with superantigens (35). 0414. E-mail address: [email protected]. The physiological significance of costimulatory signaling 6 Abbreviations used in this paper: TRAF, TNF receptor-associated factor; TNP- through CD134 has not yet been resolved. CD134 is expressed on KLH, trinitrophenyl-keyhole limpet hemocyanin; ELISPOT, enzyme-linked immu- inflammatory T cells in vivo, as in the CNS of rodents with ex- nospot; NP, nitrophenyl; CFSE, carboxyfluorescein diacetate succinimidyl diester; LN, lymph node; TMEV, Theiler’s murine encephalomyelitis virus; SEB, staphylo- perimental allergic encephalomyelitis (36), in the joints of humans coccal enterotoxin B; ES, embryonic stem. with rheumatoid arthritis (37), in the peripheral blood of rats with Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 6521 acute graft-vs-host disease (38), or on tumor-infiltrating lympho- targeted region was used on a BglII digest of the genomic DNA to identify cytes (39). CD134 is also expressed on T cells in the intestines of targeted clones. The structure of the mutant allele was subsequently con- 9 mice with inflammatory bowel disease wherein blockade of the firmed using a 3 probe on genomic DNA that had been digested with ApaI or BamHI. Approximately 1% of neor colonies were mutant at the cd134 CD134-CD134L interaction can lessen the severity of the disease locus. Chimeric mice were produced by injection of mutant ES cells into (40). Cumulatively, these expression and functional data raise the 3.5-day-old blastocysts according to standard procedures (48). These chi- possibility that CD134 signaling may help to prolong Ag-specific meras were then bred to C57BL/6 females, and germline transmission of proliferative responses or otherwise influence the persistence, dif- the cd134 mutation was confirmed by Southern blot analysis of tail DNA. CD1341/2 mice were interbred to produce the mice that were used in the ferentiation, or reactivation of effector/memory populations. experiments described below. The mRNA for CD134L is expressed in activated T cells, B cells, and also in the mouse brain and kidney (19). In humans, Flow cytometric analysis CD134L mRNA is found in the heart, skeletal muscle, pancreas, All flow cytometry was performed using a Becton Dickinson FACScan testes, and ovary (19).