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Self-Peptides Prolong Survival in Murine Autoimmunity via Reduced IL-2/IL-7-Mediated STAT5 Signaling, CD8 Coreceptor, and V2 Down-Regulation¹

Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Although 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 used mice expressing soluble OVA (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 V2/Vβ5-transgenic TCR with specificity for the OVA_257–264 peptide. Eighty-three percent of OVA/OT-I mice died during the first 2 wk of life due to multiple organ inflammation. In contrast, preventive or therapeutic OVA_257–264 peptide injections induced a dose-dependent increase in survival. Healthy survivors exhibited reductions in peripheral CD8 T cells, CD8 coreceptor, and V2 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, the soluble TCR ligand triggered multiple tolerance mechanisms in these sOVA/OT-I mice, making this treatment approach a potential paradigm for modulating human autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Cancer Institute Intramural Research Center for Cancer Research and an educational grant from the Deutsche Forschungsgemeinschaft (to J.G., Grant DFG 806-2).

² J.G. and K.E.N. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Stephen I. Katz, Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 9000 Rockville Pike, Bethesda, MD 20892. E-mail address: katzs{at}od.niams.nih.gov

⁴ Abbreviations used in this paper: Treg, regulatory T cell; K14, keratin-14; sOVA, soluble chicken OVA; SIINFEKL/OVAp, chicken OVA peptide 257–264; pSTAT5, phosphorylated STAT5; Tg, transgenic; MS, multiple sclerosis.