Microbiology & Immunology - Theses
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ItemMemory CD4 T cells in skin at steady-state and following infection( 2015)Peripheral tissues such as the skin, gut and lungs are exposed to the environment, making efficient immunosurveillance of these organs critical. This in part relies on T cells that gain access to these barrier sites. There has been an increasing interest in recent years on memory T cells permanently lodged in peripheral tissues, termed resident memory T cells or TRM. The CD8+ subset of TRM are relatively well characterized. However, there is much less information available on CD4+ T cells in peripheral compartments, especially to what extent these cells are retained in the tissue or recirculate. In this thesis, we examine CD4+ T cells in skin, with a focus on their migration patterns in the steady state as well as following the resolution of inflammation. These studies show that in mouse flank skin at steady state, the vast majority of CD4+ T cells are in equilibrium with the circulation, indicating that they constitutively migrate between the skin and blood. Viral infection or contact sensitization results in a sustained, localized increase in number of memory CD4+ T cells in skin, which is due to the generation of a long term-retained or resident population, as well as enhanced recruitment of circulating cells from the bloodstream. The hair follicle is key in mediating this numerical increase, with memory CD4+ T cells persisting in clusters surrounding these structures in conjunction with a high density of antigen presenting cells. T cells in such clusters are highly dynamic and rely on factors produced by other cells within the cluster, namely dendritic cell- and CD8+ T cell-derived CCL5, but do not appear to require persisting viral antigen. Furthermore, the majority of memory CD4+ T cells that produce the anti-viral cytokine IFNγ upon secondary infection are in close association with hair follicles. Thus, the follicle may provide an environment in which efficient T cell activation can occur in the skin, allowing for the initiation of rapid immune responses. These results highlight the complex nature of CD4+ memory T cells that are found within the skin and reveals the importance of tissue-specific factors in determining the localization of these cells within the tissue.