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

Academic Article

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: 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), peptidespecific CD8+ Tregs represent a promising therapeutic approach to autoimmune disorders.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Leavenworth JW; Tang X; Kim HJ; Wang X; Cantor H
  • Start Page

  • 1382
  • End Page

  • 1389
  • Volume

  • 123
  • Issue

  • 3