title: Differential coupling of second signals for cytotoxicity and proliferation in CD8+ T cell effectors: amplification of the lytic potential by B7.
abstract: The role of second signals delivered through B7/CD28 interactions in T cell activation is well documented. However, once CTLs are elicited, TCR-mediated cytotoxicity appears to be uncoupled from the requirement for costimulatory signals. In this study, we show an uncoupling across a broad range of concentrations of peptide, thus demonstrating that cytolysis is a TCR-mediated response that is fully independent of costimulatory signals. However, the same T cell effectors remain fully responsive to B7 engagement, which is able to amplify Ag-mediated proliferation and cytolytic capacity. B7 expression by targets results in an IL-2-mediated proliferative expansion of the effectors concurrent with the elimination of the targets. Thus, costimulation of effectors results in a vast expansion in lytic units over time, which does not occur in the absence of IL-2 or B7. Both TCR-derived and second signals appear to be necessary to achieve this result. These results suggest that B7-expressing APC or a cohort of IL-2-producing helper cells would functionally extend the duration and effectiveness of the cytotoxic response occurring in localized immune responses.
authors.affiliation: The Walter and Eliza Hall Institute, Royal Melbourne Hospital, Parkville, Australia. krummel@cmgm.stanford.edu
authors.forename: M F
authors.initials: MF
authors.lastname: Krummel
authors.forename: W R
authors.initials: WR
authors.lastname: Heath
authors.forename: J
authors.initials: J
authors.lastname: Allison
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D007376:Interleukin-2