Major Role of γδ T Cells in the Generation of IL-17+ Uveitogenic T Cells

We show that in vitro activation of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells from C57BL/6 mice immunized with an uveitogenic IRBP peptide (IRBP1-20) under TH17-polarizing conditions is associated with increased expansion of T cells expressing the gamma delta TCR. We also show that highly purified alpha beta or gamma delta T cells from C57BL/6 mice immunized with IRBP1-20 produced only small amounts of IL-17 after exposure to the immunizing Ag in vitro, whereas a mixture of the same T cells produced greatly increased amounts of IL-17. IRBP-induced T cells from IRBP-immunized TCR-delta(-/-) mice on the C57BL/6 genetic background produced significantly lower amounts of IL-17 than did wild-type C57BL/6 mice and had significantly decreased experimental autoimmune uveitis-inducing ability. However, reconstitution of the TCR-delta(-/-) mice before immunization with a small number of gamma delta T cells from IRBP-immunized C57BL/6 mice restored the disease-inducing capability of their IRBP-specific T cells and greatly enhanced the generation of IL-17(+) T cells in the recipient mice. Our study suggests that gamma delta T cells are important in the generation and activation of IL-17-producing autoreactive T cells and play a major role in the pathogenesis of experimental autoimmune uveitis. The Journal of Immunology, 2009, 183: 560-567.