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.