Two basic questions of T lymphocyte biology are addressed in this proposal: 1) How is the peripheral T cell pool, including the functionally distinct T cell subsets, maintained at homeostatic numerical levels throughout the life of an adult mouse? and 2) Which are the mechanisms for the decline of T cell functions observed with advancing age in mice and other species? The answers to the first question are essential for the elucidation of the second question. The proposed studies will use a variety of """"""""heterochronic"""""""" transplantations to determine the role of prethymic hemopoietic cell migration to thymus, the role of intrathymic expansion and selection, the role of thymic export to periphery and the role of the postthymic expansion and function of the exported cells. """"""""Heterochronic"""""""" means transplantation of """"""""young"""""""" and """"""""old"""""""" components into young or old hosts, for the assessment of the contribution of each component. Two of the AIMS will address postthymic and extrathymic T cell differentiation and renewal, especially the characterization of a postthymic progenitor compartment which is capable of extensive expansion in an antigen and thymus-independent manner in periphery. The hypothesis being that such progenitors could act as a postthymic generative compartment which is critical for normal T cell renewal guided predominantly by internal signals and not by nominal antigen. Answering the two questions above will increase both our understanding of T cell development and renewal, as well as favor a better comprehension of immunological aging.
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