Autoreactive T cells use IFNγ and Fas Ligand to clear melanocytes in vitiligo

Abstract

Abstract Vitiligo is an autoimmune disease of the skin in which melanocytes are selectively destroyed, leading to a disfiguring depigmentation. Studies by our group and others demonstrated that IFNγ-induced chemokines drive pathogenesis through the recruitment of CD8+ T cells that kill melanocytes. We examined potential mechanisms of melanocyte killing by T cells in our mouse model by performing adoptive transfer of autoreactive cells lacking IFNγ, perforin, or Fas ligand. We found that disease severity and T cell accumulation in the skin was reduced in mice that received either IFNγ KO or Fas ligand KO melanocyte-specific T cells; however, perforin was not required. We partially rescued the disease phenotype by performing 50:50 co-injections of effector molecule KO T cells with WT T cells, however KO T cells outcompeted WT cells in recruitment to the epidermis, suggesting IFNγ and Fas Ligand are needed in situ to cause disease. To determine if IFNγ signaling was directly cytotoxic to melanocytes, we used a Cre-Lox system in which the IFNγR was specifically deleted in melanocytes. Floxed/Floxed Cre+ littermates were not protected from disease, suggesting IFNγ signaling in melanocytes is dispensable for melanocyte clearance. In summary, IFNγ has pleiotropic effects in vitiligo, required both for T cell recruitment and functional killing of melanocytes. This further supports targeting IFNγ signaling for the treatment of vitiligo. In addition to IFNγ, Fas ligand is a new potential target for therapy that warrants further investigation.