Defining the mechanisms of CD4+ T cell help and roles of XCR1+ dendritic cells in CD8+ T cell responses

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Successful immune responses depend on interaction and coordination of several immune cell types. Initiation of antiviral CD8+ T cell responses is an excellent example for this as it involves the cooperation of CD4+ T cells, dendritic cells (DCs) and CD8+ T cells. In this case, naïve CD8+ T cells need to be activated by DCs and these DCs need to be licensed by CD4+ T cells for an effective response, especially in the memory phase. Although the requirement for CD4+ T cell help in CD8+ T cell responses is well established, the exact cellular and molecular mechanisms of this ‘help’ are not well understood. Recently, XCR1+ DCs, which are specialized in cross presentation of antigens to CD8+ T cells, emerged as the central DC subset involved in CD4+ T cell help to CD8+ T cells.In this project, we will investigate the roles XCR1+ DCs and CD4+ T cells in antiviral CD8+ T cells from a molecular perspective using skin herpes simplex virus (HSV) infection in mice as a model system. Skin HSV infection represents a unique infection model since HSV stays as a local infection in the skin and viral antigens has to be carried to draining lymph node by DCs, which is the case with most natural viral infections. It has been shown that this results in delayed activation of CD8+ T cells compared to CD4+ T cells as CD8+ T cells need viral antigens to be transferred to XCR1+ DCs from migratory DCs. Firstly, we will study the role of XCR1+ DCs and CD4+ T cells in CD8+ T cell priming and memory by depleting XCR1+ DCs or CD4+ T cells. Secondly, we will examine the kinetics and effects of T cell receptor signaling during the priming phase of antiviral CD8+ T cell responses against HSV. Lastly, we will analyze gene expression differences between CD8+ T cells that received CD4+ T cell help or not at the single cell level and try to identify genes expression patterns associated with enhanced memory potential. These studies will not only improve our understating of cellular and molecular events involved in the initiation of antiviral CD8+ T cell responses, but also provide valuable insights into changes induced in CD8+ T cells by CD4+ T cell help. We hope results from these studies to help us to design better vaccines that induce superior CD8+ T cells against viruses.