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

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. LIST OF SCIENTIFIC PAPERS I. IL-15 Promotes Rapid Induction of Cellular Cytotoxicity by a Subset of CD8CD49a Tissue-Resident T Cells in Human Epidermis Stanley Cheuk, Heinrich Schlums, Irène Gallais Sérézal, Samuel Chiang, Elisa Martini, Nicole Marquardt, Anna Gibbs, Andrea Introini, Marianne Forkel, Annelie Tjernlund, Jakob Michaelsson, Lasse Folkersson, Jenny Mjösberg, Marcus Ehrström, Mona Ståhle, Yenan Bryceson, Liv Eidsmo Manuscript II. Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis Stanley Cheuk, Maria Wikén, Lennart Blomqvist, Susanne Nylén, Toomas Talme, Mona Ståhle, Liv Eidsmo Journal of Immunology. 2014; 192:3111-3120 doi: 10.4049/jimmunol.1302313 Copyright 2014. The American Association of Immunologists, Inc. III. Granzyme A Potentiates Chemokine Production in IL-17 Stimulated Keratinocytes Stanley Cheuk, Elisa Martini, David Chang, Kerstin Bergh, Liv Eidsmo Manuscript IV. Genetic Variants of the IL22 Promoter Associate to Onset of Psoriasis before Puberty and Increased IL-22 Production in T Cells Pernilla Nikamo, Stanley Cheuk , Josefin Lysell, Charlotta Enerbäck, Kerstin Bergh, Ning Xu Landén, Liv Eidsmo, Mona Ståhle Journal of Investigative Dermatology. 2014, vol. 134, page. 1535-1541 CONTENTS