Phenotypic and Functional Changes in Circulating T Cells During Aging

点击翻译按钮获取中文摘要

It is well known that the ability to mount effective immune responses often declines with age. There are several, possibly interconnected shifts in T cell phenotype and function that may be either a cause or consequence of immune changes which occur in aging. The best described changes are a shift from naive to memory phenotype among both CD4 and CD8 T cells, and a decline in IL-2 production relative to cells from young subjects. The mechanisms involved in these shifts are largely unknown. To design experiments that can start to define such mechanisms, it is necessary to be able to define T cell subsets to understand the relationships among them, and what factors regulate the transition from one stage to the next. Several key cytokines, which influence the development and cytokine profile of memory T cells, are IL-2, IL-4, IFN-g, and IL-12, as well as TGFb. The unregulated expression of various inflammatory cytokines, including IL-1, IL-6, IL-8, TNF, and many CXC and CC chemokines has been shown to be involved in several disease states such as inflammation, autoimmunity, and some hematopoietic malignancies. Several studies using aged rodent and primate T cells for differential cytokine production have yielded variable results. Additional studies have demonstrated a significant shift from Th1-Th0 cells to Th2 cells over the course of aging while others have observed no phenotypic Th switch. Various studies have reported on the hyperproduction of IFN-g and TNF-a in aged versus younger animals and that these differences may relate to alterations in circulating immune cell subsets. While several human studies have also yielded variable cytokine expression results, we have initiated studies to examine such cytokine alterations (as well as the gene and protein expression of other related molecules) using several unique molecular methodologies currently in place including cytokine promoter studies, kinetic-based microarray cDNA analysis of young versus old immune cell subsets in various states of activation, RNAse protection assays, quantitative RT-PCR, nuclear binding protein analysis using DNA mobility shift analysis, and DNA methylation analysis. Using these various methods in combination, we should be able to determine if there are any alterations in cytokine production during normal and advanced accelerated (but not poor) aging (e.g., frailty) and if these changes correlate with alterations in a subjects immune status. Additional studies are underway examining the functional role(s)and cytokine profile of primary and clonal cultures of CD28-/CD28+ and CD57+/CD57- T cells isolated from rodents, humans, and primates of different ages. As these immune subpopulations are dramatically increased in the circulation during various disease states (including arthritis, AIDS, and aging), we believe that more detailed molecular and biochemical analysis of these subsets will not only yield valuable information about the immune deficits associated with aging and disease but may also lead to possible immunotherapeutic interventions to boost immune responses.