Regulated Activation of Latent-TGFb Determines Leukocyte Occupancy of the Epidermal Niche

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Abstract The epidermis of the skin is a barrier surface that serves as the front line of defense against a diverse array of potential pathogens. In addition to providing a physical barrier, the epidermis is home to several categories of long-lived immune cell types most notably Langerhans cells (LC) and CD8+ resident memory T cells (Trm). LC transport antigen acquired in the epidermis to the lymph node where they promote the development of effective T cell responses against fungi and likely other extracellular pathogens. Trm cells are a recently appreciated subset of memory T cell that are required for efficient protection against secondary Vaccinia virus and Herpes Simplex virus infections. LC and Trm are also responsible for many autoimmune diseases such as graft vs. host disease, vitiligo, and alopecia areata. Despite the importance of these cells, the mechanism(s) and factors governing their retention in the epidermal niche have been poorly described. TGFβ is released from cells as a latent form (LAP-TGFβ) and is activated by the integrins αvβ6 and αvβ8 on keratinocytes (KC). The regulated expression of αvβ6 and αvβ8 by KC directly controls epidermal residence of both Trm and LC during steady-state and after UV irradiation. This observation that the availability of the epidermal niche for leukocyte residence is determined by KC activation of TGFβ raises the possibility that pharmacologic reduction of active TGFβ could be used to alter leukocyte epidermal residence to therapeutic benefit. The goal of this competitive renewal is understand the basic biology of leukocyte retention within the epidermal niche in order to rationally translate these findings into approaches that deplete epidermal leukocytes in disease states. We propose to test the hypothesis that reduced expression of integrins by regionally segregated subsets of KC occurs in response to all inflammatory stimuli and results in loss of epidermal LC and Trm. We will also test the hypothesis that in response to inflammatory stimuli other KC subsets maintain integrin expression thereby leaving intact a local niche LC and Trm. This would allow for LC migration and open some of the epidermal niche for Trm specific for the new pathogen while also retaining LC that can repopulate the epidermis and Trm specific to previously encountered pathogens. Finally, we will test the hypothesis that therapies inhibiting active TGFβ reduce LC and Trm in patients and can ameliorate disease in an animal model of vitiligo.