Aging results in a decline in immune vigor with significant changes occurring in T lymphocyte activity. These functional changes occur as a result of compositional shifts in the peripheral T cell compartment with age. Thus, the aged animals' peripheral T cell compartment is comprised of CD4+ T cells which are phenotypically and functionally distinct from those found in young animals. It was hypothesized that these compositional changes occur progressively with age due to a lifetime of antigenic exposure, and a loss of input of newly differentiated naive"""""""" cells from the thymus. However, recent data suggests that the aged environment may play a more active role in directing the maturation of """"""""new"""""""" T cells than previously appreciated. Thus, in aged bone marrow chimeric animals, the majority of the newly arising CD4+ T cells bear the characteristic """"""""memory"""""""" markers of aged T cells and have aged functional characteristics. The present proposal will test the hypothesis that the aged thymic reticulum and/or peripheral microenvironment is able to direct the maturation of newly differentiating T cells towards the CD44hiCD45RBloL-selectinlo phenotype which produces a spectrum of lymphokines including IL-2, IL-4, IL-5, and g-IFN, characteristic of the majority of aged CD4+ T cells. The objectives of this proposal are to: characterizing the CD4+ T cells found in aged bone marrow chimeras, comparing their phenotype and function with matched subsets derived from unmanipulated young and aged mice, to determine the relative contribution of the thymic and the peripheral microenvironment to the maturation of the CD4+ Th subpopulations, and to explore several possible mechanisms which might contribute to the appearance of memory-like T cells in the aged chimeras including, lymphokine milieu, B7-1 and B7-2 expression and distribution, and post-thymic expansion of mature CD4+ populations. It is anticipated that the results shall advance our understanding of the consequence of aging on T cell differentiation allowing the design of more effective means to manipulate the immune system to achieve protective immunity both in aged individuals and others with diminished immune function such as bone marrow transplant patients, and chemotherapy recipients.
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