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Purpose.: To determine how the activation of γδ T cells affects the generation of uveitogenic αβ T cells and the development of experimental autoimmune uveitis (EAU).

Methods.: γδ T cells were isolated from B6 mice immunized with the uveitogenic peptide IRBP 1–20 and αβ T cells from immunized TCR-δ−/− mice. Resting γδ T cells were prepared by culture of separated γδ T cells in cytokine-free medium for 3 to 5 days, when they showed downregulation of CD69 expression. Activated γδ T cells were prepared by incubating resting γδ T cells with anti-γδ TCR (GL3) for 2 days. Responder αβ T cells were cocultured with immunizing antigen and antigen-presenting cells. The numbers of antigen-specific T cells expressing IL-17 or IFN-γ were determined by intracellular staining followed by FACS analysis after stimulation, with or without the addition of purified γδ T cells. The cytokines in the culture medium were measured by ELISA.

Results.: Highly enriched γδ T cells exert widely different effects on autoreactive αβ T cells in EAU, depending on the activation status of the γδ T cells. Whereas nonactivated γδ T cells had little effect on the activation of interphotoreceptor retinoid-binding protein–specific αβ T cells in vitro and in vivo, activated γδ T cells promoted the generation of uveitogenic T cells and exacerbated the development of EAU.

Conclusions.: The functional ability of γδ T cells is greatly influenced by their activation status. Activated γδ T cells exacerbate EAU through increased activation of uveitogenic T cells.