Influence of antigen dose and costimulation on the primary response of CD8+ T cells in vitro.
The influence of costimulation on the primary response of CD8+ T cells to class I alloantigens was studied with the aid of a T cell receptor transgenic model and defined peptides as antigen. With small doses of antigen, the proliferative response of CD8+ cells was high early in culture but was of brief duration and declined to low levels by day 4; this abbreviated response was associated with limited production of interleukin 2 (IL-2) and was strongly dependent upon costimulation via CD8-major histocompatibility complex class I and CD28-B7 interactions. The response to large doses of antigen was quite different in two respects. First, large doses of antigen inhibited the early (day 3) proliferative response but caused a marked elevation of the response late in culture (day 5); these altered kinetics were associated with increased production of IL-2. Second, the initial proliferative response to large doses of antigen did not require costimulation: indeed, blocking costimulation with CTLA4lg or anti-CD8 monoclonal antibody enhanced the early proliferative response. However, blocking costimulation impaired IL-2 production and prevented the late proliferative response. These findings indicate that the requirement for costimulation of T cells can be partly overcome by increasing the dose of antigen to a high level. However, costimulation plays a key role in prolonging the response, presumably by triggering strong and sustained production of IL-2.
Cai
Z
Z
Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Sprent
J
J
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D001665:Binding Sites; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology*; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D015395:Histocompatibility Antigens Class I; D018796:Immunoconjugates; D007376:Interleukin-2; D007519:Isoantigens; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept; D004247:DNA; D013936:Thymidine