Functional Conversion and Dominance of γδ T Subset in Mouse Experimental Autoimmune Uveitis

We have previously shown that activated γδ T cells have a much stronger proinflammatory effect in the development of experimental autoimmune uveitis than their nonactivated counterparts. Our present study explored γδ T cell subsets are functionally distinct in autoimmune pathogenesis and determined the pathogenic contribution of biased Vγ4⁺ γδ T cell activation in this disease. By systematically comparing two major peripheral γδ T cell subsets, the Vγ1⁺ and the Vγ4⁺ cells, we found that the Vγ4⁺ cells were readily activated in B6 mice during experimental autoimmune uveitis development, whereas Vγ1⁺ cells remained nonactivated. Cytokines that were abundantly found in the serum of immunized mice activated Vγ4⁺, but did not activate Vγ1⁺, cells. The Vγ4⁺ cells had a strong proinflammatory activity, whereas the Vγ1⁺ cells remained nonactivated when tested immediately after isolation from immunized mice. However, when the Vγ1⁺ cells were activated in vitro, they promoted inflammation. Our results demonstrated that activation is a major factor in switching the enhancing and inhibiting effects of both Vγ1⁺ and Vγ4⁺ γδ T cell subsets, and that γδ T cell subsets differ greatly in their activation requirements. Whether the enhancing or inhibiting function of γδ T cells is dominant is mainly determined by the proportion of the γδ T cells that are activated versus the proportion not activated.