Amelioration of arthritis through mobilization of peptide-specific CD8⁺ regulatory T cells

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Abstract

Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60_p216 and Qdm. We found that peptide-induced expansion of tetramer-binding CD8⁺ Tregs that recognize Qa-1–Hsp60_p216 but not Qa-1–Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (T_FH) and Th17 cells by CD8⁺ Tregs inhibited disease development. Infusion of in vitro–expanded CD8⁺ Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1–Hsp60_p216–specific CD8⁺ Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60_p216 peptide immunization. These results suggest that strategies designed to expand Qa-1–restricted (HLA-E–restricted), peptide-specific CD8⁺ Tregs represent a promising therapeutic approach to autoimmune disorders.

Authors

Jianmei W. Leavenworth, Xiaolei Tang, Hye-Jung Kim, Xiaoyang Wang, Harvey Cantor