Diminished Host Defenses and Enhanced Inflammation in Immunosenescence

Direct clinical consequences of aging of the immune system or immunosenescence include more frequent serious infections, increased incidence of diverse inflammatory diseases of the joints, skin, lungs and intestines, and decreased responses to vaccines and other beneficial immunotherapies at a time in life when they are most needed. Numerous changes in T lymphocytes or T cells with aging are major causes of the central elements of immunosenescence. Our evolving abilities to quantify accurately RNA and proteins at the cellular level, as well as many individual immune functions has permitted analyses of T cell changes at five levels: 1. Altered numbers of T cells in functional subsets. For example, reductions in naive T cells limit responses to new antigens and in regulatory T cells increase susceptibility to inflammatory diseases. 2. Defective tissue trafficking and patrolling by T cells due to migration defects. Autoantibodies to chemotactic factors or to receptors for chemotactic factors may lead to sequestration of T cells in lymph nodes, T lymphopenia, diminished mobilization of T cells to tissues, and persistent infections. 3. Modified expression of immunologically critical T cell-surface proteins. Lower levels of co-receptors necessary for T cell antigen receptor stimulation decrease responses to weak antigens, such as bacterial polysaccharides in vaccines. 4. Decreased effectiveness of functional interactions between T cells and other immune cells. Less complete T cell interactions with antigen-presenting cells result in attenuated synapses and lower adaptive immune responses. 5. Changes in levels of T cell generation of cytokines and other proteins necessary for normal immunity. Decreased generation of gamma-interferon by T cells of old men reduces activation of macrophages capable of suppressing intracellular microbes and of natural killer (NK) cells needed for eliminating neoplastic cells. More precise delineation of mechanisms of immunosenescence has led to consideration of more specific means for correction. Suppression of autoantibodies to components of T cell chemotactic systems have corrected T cell trafficking sufficiently to allow elimination of chronic infections (#2). Several classes of drugs have been identified that alter T cell generation of cytokines selectively in patterns that partially correct the immunosenescent phenotype (#5). It is hoped that minimizing immunosenescence will contribute to increased healthspan.