CD4T cells play a pivotal role in the immune response primarily directing responses of other lymphoid cells. Regulation occurs through cell-cell contact with antigen-presenting cells which directly induces signaling pathways leading to activation and function, and also results in cytokine secretion which governs the nature of the response. It is generally accepted that CD4 function in aged individuals is diminished, although the reasons and mechanisms responsible for this are not clear. Recognition of peptide/MHC complexes on APCs is a prerequisite for most aspects of CD4 function, however, additional interactions between T cell co-receptors and APC accessory molecules are required for optimal cell growth, secretion of cytokines and induction of effector function. Thus, with aging, it is possible that T cells either do not express the appropriate coreceptors for efficient response, or are hyporesponsive to signaling through these molecules. An alternative, which is not mutually exclusive, is that defects exist in provision of accessory molecule help from APCs such as B cells and macrophages. The majority of studies suggest that CD28/B7, CD40L/CD40 and LFA- 1/ICAM-1 interactions are critical for initial CD4 and APC activation in young individuals, whereas other ligand/receptor pairs, particularly Ox-40/Ox-40L and 4-1BB/4-1BBL may be crucial for later phases of primary responses and potentially for promoting secondary responses involving memory T cells. Thus all molecules represent potential targets for defects associated with aging. The studies proposed here will assess the function and roles of these molecules in T cell and APC responses from young versus old mice using AND TCR transgenic animals with which antigen-specific responses to cytochrome c can be assessed. In vitro experiments will analyze CD4 cells and assess expression and induction of CD28, CD40L, LFA-1, Ox-40 and 4-1BB with age. We will additionally assess T cell proliferative and cytokine responses induced in response to antigen using fibroblast transfectants which express one or several of the appropriate ligands, namely B7, CD40, ICAM, Ox-40L and 4-1BBL. The studies on conventional young and old transgenic mice will be complemented by assessing responses from TCR transgenic mice back- crossed with senescence accelerated mice (SAM) which show similar symptoms of aging as normal mice by which age about twice as fast. Expression and induction of the latter ligands on B cells, macrophages, and dendritic cells from young versus aged mice will be determined, and whether cross-linking these molecules on APC is defective for inducing APC function compared to cells from young animals. These studies will provide novel findings with regard to T cell-APC interactions with age and may highlight ways in which hyporesponsiveness of these cells can be corrected if ligand-receptor pairs are found that can enhance response of aged lymphocytes.
