CD28/B7 interactions deliver a unique signal to naive T cells that regulates cell survival but not early proliferation.
CD28/B7 ligation provides costimulatory signals important for the development of T cell responses. In the present study, we examined whether CD28/B7 interactions have a specialized role in the regulation of cell cycle progression and sustained T cell proliferative responses in naive T cell populations using TCR transgenic mice. CD28-mediated signaling was shown to be uniquely capable of regulating cell survival compared with TCR-mediated signaling. Increasing the strength of the TCR-mediated signal 1 increased early proliferative responses, but had no effect on sustained cell survival. In contrast, CD28 ligation, signal 2, was not required for early proliferative responses, but dramatically influenced long term T cell survival. The increased cell survival after CD28 ligation was not due to increased IL-2 production, but was linked to up-regulation of Bcl-xL. The Bcl-xL protein could not be induced following increased TCR cross-linking in the absence of CD28 signaling. In addition, survival of T cells from Bcl-xL transgenic mice was not inhibited by blocking CD28 ligation, suggesting that CD28-induced T cell survival is regulated by Bcl-xL expression. Together, these results suggest that the unique role of CD28 signaling is not to costimulate the initial activation of naive T cells, but is, in fact, to sustain the late proliferative response and enhance long term cell survival.
Sperling
A I
AI
Ben May Institute, University of Chicago, IL 60637, USA.
Auger
J A
JA
Ehst
B D
BD
Rulifson
I C
IC
Thompson
C B
CB
Bluestone
J A
JA
D000069594:Abatacept; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D002455:Cell Division; D002470:Cell Survival; D005786:Gene Expression Regulation; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D051020:bcl-X Protein
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D000069594:Abatacept