177: Maintenance of memory regulatory T cells in peripheral tissues

Abstract

The skin has unique immunological characteristics and is especially plagued by T cell mediated inflammatory disorders. To study CD4+ T cell responses to epidermal self-antigen, which are largely undefined, we established a mouse model that features tetracycline-inducible expression of chicken ovalbumin (Ova) in the epidermis under the control of the keratin K5 promoter. Expression of antigen in the skin elicits a T cell (DO11.10) dependent inflammatory dermatitis, which is associated with IFN-γ and IL-17 production by DO11 T cells. This disease develops despite the presence of high starting numbers of natural DO11 Foxp3-expressing regulatory T cells (Tregs), and, in fact, these Tregs proliferate in response to skin-Ag recognition. Tregs are activated by peripheral self-antigen to increase their suppressive function, and a fraction of these cells survive as memory regulatory T cells (mTregs). mTregs persist in nonlymphoid tissue after cessation of Ag expression and have enhanced capacity to suppress tissue-specific autoimmunity. These mTregs express specific effector memory T cell markers and localize preferentially to hair follicles in skin. Memory Tregs express high levels of both IL-2Rα and IL-7Rα. Using a genetic-deletion approach, we show that IL-2 is required to generate mTregs from naive CD4+ T cell precursors in vivo. However, IL-2 is not required to maintain these cells in the skin and skin-draining lymph nodes. Conversely, IL-7 is essential for maintaining mTregs in skin in the steady state. These results elucidate the fundamental biology of mTregs and show that IL-7 plays an important role in their survival in skin. Support: Erwin Schroedinger Fellowship from the Austrian Science Fund to I.K.G. National Institutes of Health (NIH) Grant 1K08AR062064-01, Burroughs Wellcome Career Award for Medical Scientists, and Scleroderma Research Foundation to M.D.R. NIH Grants P01 AI35297, R01 AI73656, and U19 AI56388 to A.K.A.