Cooperation of invariant NKT cells and CD4⁺CD25⁺ T regulatory cells in the prevention of autoimmune myasthenia

CD1d-restricted NKT cells and CD4⁺CD25⁺ regulatory T (Treg) cells are thymus-derived subsets of regulatory T cells that have an important role in the maintenance of self-tolerance. Whether NKT cells and Treg cells cooperate functionally in the regulation 1 of autoimmunity is not known. We have explored this possibility in experimental autoimmune myasthenia gravis (EAMG), an animal model of human myasthenia gravis, induced by immunization of C57BL/6 mice with the autoantigen acetylcholine receptor. We have demonstrated that activation of NKT cells by a synthetic glycolipid agonist of NKT cells, α-galactosylceramide (α-GalCer), inhibits the development of EAMG. α-GalCer administration in EAMG mice increased the size of the Treg cell compartment, and augmented the expression of foxp3 and the potency of CD4 ⁺CD25⁺ cells to inhibit proliferation of autoreactive T cells. Furthermore, α-GalCer promoted NKT cells to transcribe the IL-2 gene and produce IL-2 protein. Depletion of CD25⁺ cells or neutralization of IL-2 reduced the therapeutic effect of α-GalCer in this model. Thus, α-GalCer-activated NKT cells can induce expansion of CD4 ⁺CD25⁺ Treg cells, which in turn mediate the therapeutic effects of α-GalCer in EAMG. Induced cooperation of NKT cells and Treg cells may serve as a superior strategy to treat autoimmune disease.