Resident T cells in human skin : functional heterogeneity and clinical implications

Abstract: The skin forms a critical barrier against the external environment and is therefore frequently challenged by infections and subjected to immune-mediated diseases as well as malignancies. The Tissue-Resident Memory T (TRM) cell is a subset of T cells that resides at sites of previous infection in the skin and other epithelial tissues. Upon re-activation, TRM cells provide rapid, robust and localized adaptive immune defence against re-infection. The role of TRM cells in different human diseases is increasingly appreciated. This thesis aims to explore the functional capacity and regulatory mechanisms of resident T cells in human skin and their potential roles in two different immune-mediated skin diseases, vitiligo and psoriasis. PAPER I: Human skin contains heterogeneous populations of T cells. CD49a expression marks a functionally distinct subpopulation of epidermal CD8 TRM cells that are highly poised towards IFN-γ production and cytolytic function, whereas CD49a- TRM cells preferentially produced IL-17. The cytotoxic potential of CD49a+ TRM cell was specifically unleashed by IL-15 stimulation. In vitiligo, an acquired chronic depigmenting disorder of the skin, CD49a+ TRM cells accumulated in both epidermis and dermis in lesions implicating a pathogenic role of CD49a+ TRM cells. PAPER II: In psoriasis, a common chronic inflammatory skin disease, a large proportion of epidermal T cells, but not dermal T cells, expressed the pathogenic cytokines IL-17 and IL-22 during active disease (PAPER II). Upon clinical remission, T cells with pathogenic capacity were retained in the epidermis of resolved lesions. Upon reactivation, CD4 T cells responded with IL-22 production, whereas CD8 T cells with TRM cell phenotypes responded with IL-17. A model of localized disease memory based on TRM cells in resolved psoriasis was proposed. PAPER III: CD8 T cells in active psoriasis lesions expressed granzyme A, but not granzyme B or perforin. In vitro experiments showed that granzyme A specifically promotes chemokine expression in IL-17 stimulated keratinocytes. Thus, granzyme A expression in skin-resident CD8 T cells may provide proinflammatory signals in psoriasis. PAPER IV: In cohorts of Caucasian psoriasis patients and healthy controls, genetic association of variants within IL22 promoter is confined to patients with disease on-set before puberty. The risk haplotype of the IL22 promoter led to higher transcriptional activity and higher IL-22 production in CD4 T cells from psoriasis patients, underscoring the impact of genetic heterogeneity and their functional consequences in immune-mediated skin diseases. Through characterization of resident T cells in human skin in healthy and inflammatory conditions, this thesis demonstrates the functional heterogeneity of skin-resident T cells in healthy skin, vitiligo and psoriasis. Further understanding of the formation, homeostatic, regulatory and effector mechanisms of TRM cell may unveil novel therapeutic strategies and improve disease management in a wide range of skin conditions.

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