T cell memory to cell-associated antigens by a new DC subset

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DESCRIPTION (provided by applicant): Clearance of dying cells by phagocytes is generally considered to be a non-inflammatory or tolerizing process. The prevailing view is that apoptotic cells generated by normal tissue turnover are captured by DC that migrate to local lymph nodes, where they induce T cell tolerance, T cell anergy, or T cell deletion. However, phagocytosis of apoptotic cells by DC can also have pro-inflammatory effects, which in combination with the presentation of cell-associated auto-antigens to T cells- can lead to the rise of self-specific T cells. The mechanisms that govern the decision between the induction of tolerizing and pro-inflammatory T cell responses are not only relevant for our understanding of the development and progression of autoimmune disorders, but are also crucial for the fields of transplantation and tumor cell vaccination that all deal with cell- death and induction of self-reactive T cells to cell-associated antigens. Current research suggests that the balance between immune-suppressive and pro-inflammatory responses is greatly affected by the type of phagocytic cell that is involved and the milieu created by this phagocytosing cell. We recently identified a novel DC subset, nDC CD11c+CD11b-CD4-CD81-, that in contrast with other cross- presenting DC subsets potently (cross-)primes both CD4+ and CD8+ T cells to cell-associated antigens. This nDC subset produces type I IFNs after uptake of apoptotic material that acts as adjuvant in the priming of T cells. CD8+T cells primed by these nDC do not become tolerant or anergic, but display enhanced primary clonal expansion and produce more cytokine/effector molecules on a per cell base. In addition, CD8+T cells primed by nDC show greater capacity for secondary expansion and memory development in vivo and in vitro. In this study we seek to determine (i) how priming by nDC affects the instructional program in CD8+ T cells, and (ii) how type I IFN production by the nDC upon acquisition of apoptotic material affects CD8+T cell fate. PUBLIC HEALTH RELEVANCE Cross-presentation of cell-associated antigens by dendritic cells (DC) generally leads to the induction of T cell tolerance, but in some cases to potent T cell priming. In this project we will study how presentation of cell- associated antigens -derived from dying cells- by different DC subsets affects the phenotype and fate of antigen-specific CD8+T cell responses.