The effects of B7-dependent costimulation on T cell division and survival in vivo and in vitro are dependent on antigen concentration.
We used 5-(and 6-) carboxyfluorescein diacetate succinimidyl ester labeled TCR-transgenic CD4(+) T cells to investigate the contribution of B7 costimulation to T cell activation and clonal expansion. B7 costimulation was blocked with the fusion protein cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-Ig, which prevents the interaction of B7 with its receptor CD28 on T cells. CTLA4-Ig had different effects depending on the density of antigen (Ag)/MHC ligands available by T cells. In the presence of CTLA4-Ig, tenfold higher concentrations of Ag were required for T cells to undergo cell division in vitro. At high Ag concentrations, T cell division occurred at comparable rates whether in the presence or absence of CTLA4-Ig; however, T cell survival and clonal expansion were strongly inhibited. Addition of IL-2 restored T cell survival but not responsiveness to low doses of Ag. In vivo, B7 costimulation was similarly required for the survival of Ag-specific T cells but not for cell division in response to high amounts of Ag. Thus, B7 costimulation regulates CD4(+) T cell responses by promoting cell division in the presence of limiting amounts of Ag, and by protecting T cells from the onset of apoptosis.
Lumsden
Joanne M
JM
Malaghan Institute of Medical Research, Wellington, New Zealand.
Prasad
Simon J
SJ
Peach
Robert J
RJ
Ronchese
Franca
F
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D015703:Antigens, CD / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003574:Cytochrome c Group / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000941:Antigens; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D003574:Cytochrome c Group; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D013936:Thymidine