Three basic questions on T lymphocyte biology are addressed in this proposal: 1) How is the peripheral T cell pool, including the functionally distinct CD4 and CD8 T cell subsets, maintained at homeostatic """"""""constant"""""""" levels throughout the life of an adult mouse? 2) What is the composition and function of the atrophic thymus in adult mice? and 3) Which are the mechanisms for the decline of T cell functions with aging observed in mice? Answers to the first two questions are essential for the elucidation of the third one. The proposed studies use a variety of """"""""heterochronic"""""""" models, with thymus grafts and thymus in situ, to determine the roles of: prethymic hemopoietic cell migration to thymus (Aim 1), intrathymic expansion and thymic export to periphery (Aim 2) and postthymic expansion and maintenance of the exported T cells at steady state levels, depending on cell input (Aim 3). """"""""Heterochronic"""""""" means transplantation of """"""""young"""""""" and """"""""old"""""""" components into young or old hosts, and assessment of each component. The studies will use only syngeneic or congenic combinations. Prethymic or postthymic cells with recognizable markers, such as chromosome, surface antigens or retroviral vector inserted genes (such as beta-galactosidase lacZ) will be used for the population analysis, especially the characterization of postthymic progenitors capable of extensive antigen and thymus independent expansion in periphery, when injected in thymus deprived hosts. The lacZ marker allows recognition of cells by histochemical methods and analysis of progeny by vector integration sites. The working hypothesis is 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. The role of some lymphokines, including tumor necrosis factor (TNF) in T cell maintenance will also be studied. Answering the 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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