The generation of memory antigen-specific cytotoxic T cell responses by CD28/CD80 interactions in the absence of antigen

The interaction of co-stimulatory molecules CD80/CD86 on antigen-presenting cells with CD28 on naive CD8⁺ cytotoxic T (Tc) cells is understood to be critical in the induction of Tc effectors. CD80 is capable of providing signal 2 for the activation of Tc cells, but has no effect if encountered in the absence of specific peptide/MHC complexes (signal 1). We have found that CD80 presented in vitro to resting memory viral-immune or alloimmune Tc cells can provide sufficient stimulus for the generation of effector Tc cells in the absence of specific antigen, the peptide/MHC class I complex. Effector Tc cells generated in vitro from influenza- or class I alloantigen-primed mice by co-stimulation in the absence of antigen require exogenous interleukin (IL)-2 signaling via the cell surface-expressed IL-2 receptor or, under conditions of IL-2 blockade, exogenous IL-7. Activation of memory Tc cells by signal 1 and 2 is independent of IL-2 and IL-7. Although memory influenza-immune Tc cells did respond to CD80 in the absence of antigen, the presence of antigen +CD80 enabled an earlier induction of these Tc cells and they retained their lytic activity in vitro over a longer time period. The capacity of memory Tc cells to be activated by signal 2 alone provides one explanation for the observed heterogeneity of phenotype of memory T cells in vivo and a possible mechanism for the maintenence of memory in the absence of persisting antigen.