Medicine (St Vincent's) - Theses
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ItemCharacterization of T cell populations in human skin( 2016)Human skin serves as a primary barrier to pathogenic and environmental assault. As part of the frontlines of the skin immune system, normal skin contains a vast number of T cells. With advances in immunofluorescent staining, confocal microscopy and fluorescence activated cell sorting, enumeration and characterization of these cutaneous T cells can now be performed with improved accuracy. Furthermore, several subsets of T cells, including mucosal-associated invariant T (MAIT) cells and resident memory T (TRM) cells, have only recently been described and their exact distribution in normal human skin remains to be elucidated. The relationship of T cells to hair follicles, ubiquitous appendages in human skin, also requires further investigation. This dissertation presents a comprehensive assessment of the distribution and composition of major T cell subsets in human skin at steady state. The gene expression profiles of skin and blood T cells were compared to determine a transcriptional signature for cutaneous T cells. We also conducted a preliminary investigation of the novel T cell subsets MAIT cells and TRM, exploring their presence in normal and diseased skin. Finally, we used a targeted laser capture microdissection approach to study chemokine expression in healthy hair follicles and in the autoimmune hair loss condition alopecia areata. Our findings reconfirm the strikingly anisotropic arrangement of T cells in normal human skin, with preferences for superficial perivascular and perifollicular localization. A resident cutaneous population of MAIT cells was found, with increased frequency in the blistering skin condition dermatitis herpetiformis. Surprisingly, a strong disparity was observed between the transcriptional profiles of skin-tropic T cells isolated from normal blood and skin. As the skin-derived T cells showed significant enrichment for genes from the TRM transcriptional core signature, we hypothesized that the skin may contain additional as-yet undefined TRM or TRM-like populations. Analysis of alopecia areata hair follicles revealed the presence of perifollicular T cells of a TRM phenotype that persisted long after active hair loss had ceased. Gene expression studies of laser microdissected follicles further highlighted transcriptional abnormalities in alopecia areata follicles that spanned the natural history of the disease. The results from this dissertation form a foundation for further study of conventional and emerging T cell subsets in skin and hold implications for the pathogenesis of the dermatological diseases dermatitis herpetiformis and alopecia areata.