Self-Peptides Prolong Survival in Murine Autoimmunity via Reduced IL-2/IL-7-Mediated STAT5 Signaling, CD8 Coreceptor, and Vα2 Down-Regulation

While the pathogenic role of B cells and CD4 T cells has been studied extensively, less is known about the role of CD8 T cells in autoimmunity and self-tolerance. To evaluate the role of CD8 T cells in autoimmunity and its modulation using self-peptides, we utilized mice expressing soluble ovalbumin (sOVA) under control of the keratin-14 promoter. Spontaneous autoimmunity occurred when sOVA-mice were crossed with OT-I mice, whose CD8 T cells carry a Vα2/Vβ5-transgenic T cell receptor with specificity for the OVA257-264-peptide (OVAp). 83% of OVA/OT-I mice died during the first two weeks of life due to multiple-organ inflammation. In contrast, preventive or therapeutic OVAp injections induced a dose-dependent increase in survival. Healthy survivors exhibited reductions in peripheral CD8 T cells, CD8-coreceptor- and Vα2-expression. Furthermore, CD8 T cells from healthy mice were anergic and could not be activated by exogenous IL-2. A block in IL-2/IL-7 signaling via the STAT5-pathway provided the basis for low surface expression of the CD8-coreceptor and failure of IL-2 to break CD8 T cell anergy. Thus, soluble T cell receptor ligand triggered multiple tolerance mechanisms in these sOVA/OT-I mice, making this treatment approach a potential paradigm for modulating human autoimmune diseases.