DEVELOPMENT &CONTROL OF NATURAL ANTOREACTIVE B T CELL

Institute For Cancer Research, Philadelphia PA

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Abstract

The mechanism for generation of autoreactive alpha beta T cells in normal mice and their physiological significance in the immune system are not yet established. We have previously reported that generation of alpha beta T cells with reactivity to autologous cells occurs naturally and that such cells can be identified as a small alpha beta CD4+ T cell subset, termed "Thy0" in the thymus. Thy0 cells promptly secrete a diverse array of cytokines upon incubation with autologous cells, particularly class II+ cells. Understanding the developmental mechanism and the fate of such autoreactive T cells is important since these cells have the potential to influence the immune response if appropriately activated. Our recent data suggest that NK1.1+ alpha beta cells, capable of TH2 cell induction and cytotoxicity, may represent the ultimate fate of Thy0. However, since there is an emerging consensus that the NK1.1+ alpha beta cell subset represents a third T cell "lineage", recognizing the non-classical class I molecule CD1 as a ligand, our observation of class II dependent cell activation is difficult to reconcile. Therefore, we propose to investigate the mechanism of autoreactive alpha beta T cell generation and developmental relationship between Thy0 and NK1.1+ alpha beta T cell populations. Specifically, we will resolve whether the positive selection of autoreactive cells is accounted for simply because the cell possesses an intermediate TCR affinity/avidity or instead results from a unique selection mechanism operating during early ontogeny (Aim 1 and 20. Furthermore, we will determine whether the NK alpha beta cell phenotype results from preferential survival of autoreactive T cells influenced by a balance of receptor-ligand mediated signals (Aim 3 and 4). These investigations encompass our long-term goal to understand the developmental mechanism and functional significance of natural autoreactive lymphocytes in the immune system.