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

The Journal of clinical investigation (Impact Factor: 13.22). 02/2013; 123(3). DOI: 10.1172/JCI66938
Source: PubMed


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.

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Available from: Jianmei W Leavenworth, Feb 06, 2015
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    • "Sharing some commonalities with CD4+ cells, TCDD-activated Ahr enhances CD25 expression on CD8+ cells, which induces a CTL phenotype termed CD8+ Tregs that are capable of suppressing responder T cells and proinflammatory cytokines [69]. Deregulation of these cells has been recently linked to certain animal models of autoimmunity such as EAE [70], UC [71], and CIA [72]. However, the significance of Ahr in these cells in relevance to autoimmunity is awaiting further investigation. "
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