L and Bcl-X Staying Alive

Staying Alive: T Cell Costimulation, CD28, and Bcl-x L Tania H. Watts This information is current as J Immunol 2010; 185:3785-3787; ; of September 25, 2021. doi: 10.4049/jimmunol.1090085 http://www.jimmunol.org/content/185/7/3785 Downloaded from References This article cites 39 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/185/7/3785.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 25, 2021 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Staying Alive: T Cell Costimulation, CD28, and Bcl-xL Tania H. Watts he survival of lymphocytes is tightly regulated at each cemented the role of CD28 as a key receptor for signal 2 for stage of their lifespan. Although this may seem ob- T lymphocyte activation (14–19). T vious to us today, prior to the early 1990s, the focus of At the time of the studies of Boise et al. (2), it had been most studies of T lymphocyte activation emphasized the established that CD28 engagement could induce high level regulation of cellular proliferation, with studies of cell death IL-2 production by increasing both the transcription of the focused on apoptosis during development (1). The paper of IL-2 gene (20) and the stability of its message (21). There was Boise et al. (2), highlighted in this Pillars of Immunology article, also evidence that signals through the TCR in the absence of provided two important new insights that brought to the accessory cells could induce apoptosis of mature T cells and forefront the concept that T cell costimulation provides critical that this could be prevented by addition of IL-2 (22–24). In survival signals to T cells. The first important insight was that contrast, mitogen-activated lymphocytes were resistant to Downloaded from costimulation through CD28 induces intrinsic survival signals irradiation-induced apoptosis (25), leading Boise et al. to in T cells, independently of the exogenous proliferative/survival suspect a role for costimulation in prevention of T cell death. signals induced by IL-2. Secondly, Boise et al. provided evi- At the same time, data were emerging suggesting that there dence that the intrinsic survival signal induced by CD28 was were intrinsic mechanisms that regulated lymphocyte survival. distinct from the homeostatic survival mechanisms in place in The Bcl-2 gene had been identified through its aberrant ex- resting T cells. pression in B cell lymphomas with the t(14;18) translocation http://www.jimmunol.org/ The two signal model of lymphocyte activation, as con- (reviewed in Refs. 26 and 27). Bcl-2 overexpression allowed ceptualized for T lymphocytes by Lafferty (3), posited that the survival of lymphocytes upon growth factor withdrawal “both antigen and an inductive stimulus are required for and had recently been shown to be critical for lymphoid T cell activation and neither factor alone induces detectable homeostasis (27, 28). Importantly, Boise et al. (2) had just T cell activation.” It was already recognized in the 1970s that cloned a homolog of Bcl-2, Bcl-xL, whose overexpression this inductive process required a metabolically active acces- could replace Bcl-2 in sustaining survival of IL-3–dependent sory cell. This concept was revisited again in the 1980s by cells upon cytokine withdrawal (29). These findings led Boise Jenkins and Schwartz (4) and by Quill and Schwartz (5), who et al. (2) to hypothesize that the costimulatory signal induced by guest on September 25, 2021 showed that provision of signal 1 without signal 2 (using ei- by CD28 might induce intrinsic survival signals in activated ther fixed APCs or purified MHC class II in planar mem- T cells. branes) led to clonal inactivation of murine T cell clones. To test this concept, the authors first demonstrated that These findings invigorated the search for the key molecule(s) activated T cells were more resistant than resting lymphocytes that could provide signal 2. However, it was an independent to cell death induced by gamma irradiation. The advantage of line of research on the characterization of human T cell sur- this approach was that irradiation could induce cell death face molecules using monoclonal Abs that led to the identi- independently of surface death receptors whose expression fication of CD28 as a key receptor for signal 2 for naive T cell could change with activation. Initial experiments showed that activation. Costimulation of T cells through the TCR and T cells activated by plate-bound anti-CD3 were more resistant CD28 greatly increased human T cell proliferation and IL-2 to cell death than cells left untreated, independently of the in- production (reviewed in Ref. 6). These findings were soon clusion of anti-CD28 in the stimulation. However, if they followed by the identification of the ligands for CD28, now washed the cells to remove accumulated cytokines in the super- known as B7.1 and B7.2 (7–11), as well as a second, inhib- natant, “the anti-CD3 only” cultures were more radiation itory, B7 binding receptor, CTLA-4 (12). Although not all sensitive, whereas the anti-CD3 plus anti-CD28–treated cul- immune responses were found to be CD28 dependent (13), tures remained resistant to irradiation-induced death. Addi- studies showing that CD28–B7 interactions could costimulate tion of IL-2 restored the resistance of the anti-CD3–treated T cells and prevent T cell clonal anergy, as well as the dra- cells, confirming that IL-2 could provide an extrinsic survival matic inhibitory effects of B7 blockade by CTLA-4-Ig in vivo, signal to activated T cells, but also demonstrating that costimulation reduced the requirement for IL-2 in T cell survival. However, at this stage they could not rule out that the anti- Department of Immunology, University of Toronto, Toronto, Ontario, Canada CD28 treatment was simply increasing the amount of IL-2 pro- T.H.W. holds the Sanofi Pasteur Chair in Human Immunology at the University of duced, rendering the washout experiment less effective. Toronto. Boise et al. (2) next went on to examine the induction of Address correspondence and repint requests to Dr. Tania H. Watts, Department of Bcl-2 and Bcl-x by anti-CD3 and anti-CD28. When exam- Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail L address: [email protected] ined at the protein level, Bcl-2 levels were constant in resting versus activated T cells, whereas Bcl-xL protein was mildly Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 induced by anti-CD3 and strongly induced by anti-CD3 plus www.jimmunol.org/cgi/doi/10.4049/jimmunol.1090085 3786 PILLARS OF IMMUNOLOGY anti-CD28. Although Bcl-2 message increases with T cell ac- 3. Lafferty, K. J., and J. Woolnough. 1977. The origin and mechanism of the allograft reaction. Immunol. Rev. 35: 231–262. tivation, it is not regulated by CD28 and the mRNA appears 4. Jenkins, M. K., and R. H. Schwartz. 1987. Antigen presentation by chemically to increase to maintain steady state levels of Bcl-2 protein as modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165: 302–319. the cells divide. Moreover, CD28 costimulation, but not stim- 5. Quill, H., and R. H. Schwartz. 1987. Stimulation of normal inducer T cell clones ulation through other surface molecules, such as LFA-1 or with antigen presented by purified Ia molecules in planar lipid membranes: specific CD2 or addition of exogenous IL-2, could augment Bcl-x induction of a long-lived state of proliferative nonresponsiveness. J. Immunol. 138: L 3704–3712. expression. Addition of CTLA-4-Ig to the cultures resulted 6. Linsley, P. S., and J. A. Ledbetter. 1993. The role of the CD28 receptor during T cell responses to antigen. Annu. Rev. Immunol. 11: 191–212. in the complete abrogation of Bcl-xL induction by anti-CD3. 7. Linsley, P. S., E. A. Clark, and J. A. Ledbetter. 1990. T-cell antigen CD28 mediates Thus, the low level induction of Bcl-xL by anti-CD3 alone adhesion with B cells by interacting with activation antigen B7/BB-1. Proc. Natl. may have been due to the presence of B7 on the activated Acad. Sci. USA 87: 5031–5035. 8. Freeman, G. J., A. S. Freedman, J. M. Segil, G. Lee, J. F. Whitman, and T cells. The peak induction of Bcl-xL expression by CD28 L. M. Nadler. 1989. B7, a new member of the Ig superfamily with unique ex- was coincident with the peak resistance to exogenous death pression on activated and neoplastic B cells. J. Immunol. 143: 2714–2722. signals induced by FAS cross-linking. Moreover, the overex- 9. Freeman, G. J., J. G. Gribben, V. A. Boussiotis, J. W. Ng, V. A. Restivo, Jr., L. A. Lombard, G. S. Gray, and L. M. Nadler. 1993. Cloning of B7-2: a CTLA-4 pression of Bcl-xL prevented apoptosis induced by FAS, anti- counter-receptor that costimulates human T cell proliferation.

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