Altered expression and function of P-glycoprotein (170 kDa), encoded by the MDR 1 gene, in T cell subsets from aging...

Aging is associated with progressive T cell-mediated immune deficiency, increased frequency of infections, and autoimmune phenomena. P-glycoprotein (P-gP), a 170-kDa glycoprotein, is a member of a superfamily of ATP-binding cassette transport proteins that has been shown to express on cells of the immune system and suggested to play a role in secretion of certain cytokines and cytotoxic molecules. Because aging is associated with altered secretion of cytokines, in this investigation we examined the expression and function of P-gP in CD4+ and CD8+ T cells and their "memory" and "naïve" subpopulations in peripheral blood from healthy aging and young subjects. P-glycoprotein expression was analyzed at the protein levels by dual- or triple-color flow cytometric analysis, using monoclonal antibodies against P-gP (MRK16), and at the mRNA level by quantitative reverse-transcriptase polymerase chain reaction. The efflux function of P-gP was measured by intracellular accumulation of rhodamine-123 (Rh123; a substrate for P-gP) in the presence or absence of cyclosporin A (which binds to P-gP and inhibits its efflux function). The data show increased expression of P-gP at both the protein and the mRNA levels in aging lymphocytes. Increased P-gP expression, at the protein level, was also observed in naïve cell subpopulations from aging CD4+ and CD8+ T cell subsets compared to those from young controls. An increase in P-gP function, as measured by the ability of T cell subsets to efflux Rh123, was observed in aging CD4+ and CD8+ T cell subsets and their naïve and memory subpopulations. These data suggest that altered P-gP expression and function in aging may play a role in changes in immune response, including cytokine secretion, associated with human aging.