Differential role of CTLA-4 in regulation of resting memory versus naive CD4 T cell activation.
Regulation of peripheral T cell responses is critical for preserving self tolerance. Memory T cells have a lower threshold for activation through the TCR and are thought to be less dependent on costimulation than naive T cells, suggesting a requirement for more stringent regulation of memory T cells. We have recently shown that CD4 engagement apart from the TCR results in the inactivation of memory, but not naive, CD4 T cells. We show here that this inhibition requires ligation of CTLA-4, in that blocking CTLA-4-B7 interactions restores memory CD4 T cell responsiveness. Early signaling through CTLA-4 is possible because resting memory, but not naive, CD4 T cells contain intracellular stores of CTLA-4 that are continuously recycled between the cytoplasm and the cell surface. This mechanism ensures that low intensity TCR engagements, which are thought to be important for peripheral T cell longevity, do not cause memory T cell activation but instead raise their threshold for costimulatory signals. This may give memory T cells an extended lifespan with a reduced risk of inappropriate activation.
Metz
D P
DP
Immunobiology Section, Yale University School of Medicine, New Haven, CT 06510, USA.
Farber
D L
DL
Taylor
T
T
Bottomly
K
K
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000494:pharmacology; D001666:Binding Sites, Antibody; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D007108:Immune Tolerance / Q000276:immunology; D018796:Immunoconjugates; D007156:Immunologic Memory / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D011961:Receptors, Fc / Q000378:metabolism; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011961:Receptors, Fc; D000069594:Abatacept