Bovine and human insulin activate CD8(+)-autoreactive CTL expressing both type 1 and type 2 cytokines in C57BL/6 mice

CD8(+) T cells down-regulate a variety of immune responses. For example, po rcine and human insulin do not stimulate Abs in C57BL/6 mice because CD8(+) .T cells inhibit CD4(+) helper T cells. By contrast, bovine insulin induces Ab in C57BL/6 mice, and removal of CD8(+) T cells does not alter this resp onse. This raises the question of whether porcine, but not bovine, insulin activates CD8(+) T cells or whether both insulins activate CD8(+) T cells b ut CD4(+) helper T cells are differentially inhibited by them. In this stud y, we show that insulin-specific CD8(+) CTL can be cultured from C57BL/6 mi ce primed with either bovine or human insulin in CFA, Thus, exogenous Ags, besides OVA, induce CD8(+) CTL when administered in an adjuvant, suggesting this is a typical response. These CTL are H-2K(b) restricted and produce I L-5, IL-10, IFN-gamma, and small amounts of IL-4, which is distinct from IF N-gamma and TNF-alpha that are typically secreted by virus-specific CTL, Mo reover, the CTL primed with either bovine or human insulin recognize an A-c hain peptide that is identical to the mouse insulin sequence, That foreign proteins, which are closely related to self-proteins, activated autoreactiv e, CD8(+) T cells in vivo is a novel finding. It raises the possibility tha t self-reactive CTL may be activated by cross-reacting Ags and once activat ed they might participate in autoimmunity, These results also suggest that down-regulation of insulin-specific responses by autoreactive CD8(+) T cell s is most likely due to the differential sensitivity of bovine and human in sulin-specific CD4(+) T cells.