Characterisation and functional analysis of factors that define tissue-resident memory T cells and contribute to their sessile phenotype

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The adaptive immune response generates antigen-specific lymphocytes which recognise the pathogen and contribute to its clearance. During the subsequent memory phase most antigen-experienced T cells such as central memory and effector memory T cells (Tcm and Tem) re-circulate through the body in search of the pathogen. However, as demonstrated in various infectious models an additional CD8+ memory T cell population looses its migratory capacities and resides at epithelial barriers. These cells have been termed tissue-resident memory T cells (Trm) and have been identified in various organs as CD8+, CD44high, CD103+, CD69+, VLA-1+ lymphocytes. For example, in the murine herpex simplex virus (HSV) skin infection model long-lived Trm persist in the epidermis without re-distributing to other organs. Upon secondary infection with the virus Trm confer additional protection in regions where they are lodged, resulting in rapid pathogen control. As the existence of Trm and their protective function has only been recognised in recent years, many issues remain unresolved. For instance, it is not clear which factors contribute to the Trm formation or the factors that maintain their survival in peripheral tissues. To address these issues, my project will take advantage of the murine HSV infection model to generate Trm. Several candidate genes associated with Trm formation will be identified and then tested in knockout models and others for their role in generating as well as maintaining Trm as a non-migratory memory population. Additionally, microarray analysis of Trm from different tissues will address whether additionally any tissue-specific factors are responsible for the development and retention of Trm in various organs.Due to the fact that Trm express a specific set of markers and are sessile, the emerging consensus is that they form a unique subpopulation distinct from Tcm and Tem. In order to compare the similarities and differences between Trm, Tcm and Tem I will perform microarray analysis of the different populations in the HSV model. Upon identification of genes specifically expressed in Trm, selected candidates will be knocked down in naïve CD8+ T cells using RNAi technology. Subsequently, the contribution of these adoptively transferred T cells to the Trm pool will be tested. Overall, this work aims to elucidate the major determinants which distinguish Trm from other T cell memory populations and contribute to the resident Trm phenotype. The insight gathered throughout this study will enchance our understanding of this novel memory T cell population and will presumably aid in the development of advanced T cell based vaccines.