A theory of aging hypothesizes that immunologic senescence and dysregulation leads to autoimmune tissue damage that is of major importance in the aging process. Thymic involution and a number of immunologic dysfunctions, particularly in T-cells, have been associated with aging, but the mechanisms leading to these manifestations are unknown. The overall objective of this proposal is to determine whether aging and thymic involution are associated with changes in T-cell antigen receptor (TCR) variable (V) region gene repertoire, particularly abnormalities in intrathymic positive and negative selection processes. The proposed studies will assess total TCR Vbeta expression patterns in primary lymphoid organs, and T-cell subsets thereof, of young and aged murine inbred strains of several H-2 and Mls backgrounds using a qualitative and quantitative RNAase protection assay. The """"""""idiotypic"""""""" repertoire of such mice to defined T-cell-dependent epitopes will also be assessed by cloning TCR Valpha and Vbeta elements from corresponding T-cell hybridomas. Self-renewal capacity and re-emergence of Vbeta clonotypes upon their elimination with Vbeta-specific monoclonal antibodies in thymectomized or non-thymectomized young and aged mice will be evaluated, and the effects of environmental """"""""superantigens"""""""" in shaping in vivo the TCR repertoire of mice with involuted thymuses will be ascertained. The contribution of the thymic microenvironment versus bone marrow precursor composition in age-related TCR repertoire changes, if any, will be examined in irradiated mice of various ages reconstituted with syngeneic bone marrows from aged mice to inhibit autoimmune disease development in appropriate murine models will be compared. Moreover, TCR Vbeta gene repertoires in peripheral lymphocytes of humans of both sexes and of various ages will be analyzed.
