This is a competitive renewal of a proposal whose initial aims were to assess the T lymphopoietic capability of hematopojetic stem cells in the context of HIV disease. In the conduct of those studies we established a three dimensional matrix system which is efficient at inducing T cell differentiation and which, by virtue of its structure, creates an ex vivo organ-like structure or organoid. In the process of developing this system we observed cell egress which was differentiation stage-specific and which was inhibitable by pertussis toxin. Hypothesizing that this represented chemokine mediated directional movement of cells down a concentration gradient, we documented that such cell movement could be caused by at least one known chemokine, SDF-1a at high concentrations, and by a distinct protein fraction derived from thymic stroma. The phenomena of lymphocyte movement away from a concentration gradient has not been previously characterized and we termed this process fugetaxis (fugere: to flee from; taxis; movement). This proposal seeks to build upon the identification of fugetaxis. It will address the following specific aims based on preliminary data to support each aim: 1. Evaluate a role for fugetaxis in normal physiology. We will assess the role of active movement down a concentration gradient in the egress of mature cells from the thymus during T lymphopoiesis. 2. Determine if fugetaxis is induced by a family of proteins. We will identify the non-SDF-l fugetactic factor produced by thymic stroma capable of inducing mature T cell movement down a concentration gradient. 3. Define a role for fugetaxis in a pathologic state. We will test the potential for active T cell movement away from a fugetactic signal to participate in the pathophysiology of HIV disease.
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