[HTML][HTML] Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells
The Journal of clinical investigation, 2013•Am Soc Clin Investig
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: Hsp60p216 and Qdm. We
found that peptide-induced expansion of tetramer-binding CD8+ Tregs that recognize Qa-1 …
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: Hsp60p216 and Qdm. We
found that peptide-induced expansion of tetramer-binding CD8+ Tregs that recognize Qa-1 …
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: Hsp60p216 and Qdm. We found that peptide-induced expansion of tetramer-binding CD8+ Tregs that recognize Qa-1–Hsp60p216 but not Qa-1–Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (TFH) 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–Hsp60p216–specific CD8+ Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60p216 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.
The Journal of Clinical Investigation