Cytokine priming enables triggering of autoreactive CD8 T lymphocytes by low affinity TCR ligands (83.7)

Abstract

Abstract The cellular and molecular events preceding the initial activation of autoreactive CD8 T cells in several autoimmune diseases remain unclear. Recent reports have implicated IL-6, IL-21, IL-15 and IL-7 in the triggering of autoreactive CD8 T cells in mouse models of autoimmune diseases. We have shown that IL-21 and IL-6 synergize with IL-7 or IL-15 to induce antigen-independent proliferation of naive CD8 T cells, with a concomitant increase in antigen responsiveness. We postulated that the cytokine-induced augmentation of TCR sensitivity (referred herein as ‘cytokine priming’) might enable stimulation of potentially autoreactive CD8 T cells by low affinity self antigens. Here, we show that cytokine priming enables naive TCR transgenic CD8 T cells to respond to low affinity TCR ligands, resulting in proliferation and acquisition of effector functions. We have used a transgenic mouse model of autoimmune type 1 diabetes to show that cytokine-primed autoreactive CD8 T cells acquire the capacity to cause disease following stimulation with weak TCR agonists, and that the diabetogenic potential of these cells is dependent on the continuous availability of IL-15. These findings demonstrate a novel mechanism by which cytokines contribute to the triggering of autoreactive CD8 T cells and have important implications for autoimmune diseases associated with infections and chronic inflammation.