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Bovine and Human Insulin Activate CD8⁺-Autoreactive CTL Expressing Both Type 1 and Type 2 Cytokines in C57BL/6 Mice¹

Hakling Ma^*, Yong Ke^2,*, Qingqin Li^3, and Judith A. Kapp^4,*

^* Departments of Ophthalmology and Pathology and Winship Cancer Center, and Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322

CD8⁺ T cells down-regulate a variety of immune responses. For example, porcine 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 response. This raises the question of whether porcine, but not bovine, insulin activates CD8⁺ T cells or whether both insulins activate CD8⁺ T cells but CD4⁺ helper T cells are differentially inhibited by them. In this study, we show that insulin-specific CD8⁺ CTL can be cultured from C57BL/6 mice 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 IL-5, IL-10, IFN-, and small amounts of IL-4, which is distinct from IFN- and TNF- that are typically secreted by virus-specific CTL. Moreover, the CTL primed with either bovine or human insulin recognize an A-chain peptide that is identical to the mouse insulin sequence. That foreign proteins, which are closely related to self-proteins, activated autoreactive, CD8⁺ T cells in vivo is a novel finding. It raises the possibility that self-reactive CTL may be activated by cross-reacting Ags and once activated they might participate in autoimmunity. These results also suggest that down-regulation of insulin-specific responses by autoreactive CD8⁺ T cells is most likely due to the differential sensitivity of bovine and human insulin-specific CD4⁺ T cells.

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