Antigen presentation by keratinocytes directs autoimmune skin disease

The antigen-presenting cells that initiate and maintain MHC class II-associated organ-specific autoimmune diseases are poorly defined. We now describe a new T cell antigen receptor (TCR) transgenic (Tg) model of inflammatory skin disease in which keratinocytes activate and are the primary target of autoreactive CD4(+) T cells. We previously generated keratin 14 (K14)-A(beta)(b) mice expressing MHC class If only on thymic cortical epithelium. CD4(+) T cells from K14-A(beta)(b) mice fail to undergo negative selection and thus have significant autoreactivity. The TCR genes from an autoreactive K14-A(beta)(b) CD4 hybridoma were cloned to produce a TO Tg mouse, 2-2-3. 2-2-3 TCR Tg cells are negatively selected in WT C57BL/6 mice but not in 2-2-3/K14-A(beta)(b) mice. Interestingly, a significant number of mice that express both the K14-A(beta)(b) transgene and the autoreactive 2-2-3 TCR spontaneously develop inflammatory skin disease with mononuclear infiltrates, induction of MHC class II expression on keratinocytes, and T helper 1 cytokines. Disease can be induced by skin inflammation but not solely by activation of T cells. Thus, cutaneous immunopathology can be directed through antigen presentation by tissue-resident keratinocytes to autoreactive TCR Tg CD4(+) cells.