Increased IL-21 secretion by aged CD4+T cells is associated with prolonged STAT-4 activation and CMV seropositivity

Advancing age leads to significant decline in immune functions. IL-21 is produced primarily by T follicular helper (Tfh) cells and is required for effective immune cell functions. Here we compared the induction of IL-21 in aged and young subjects. Our investigation demonstrates that CD4+T cells from healthy elderly individuals (age ≥ 65) secreted significantly higher levels of IL-21 on priming with aged and young dendritic cells (DC). Though the aged and young DCs secreted comparable levels of IL-12 on stimulation with anti-CD40 antibody and LPS, culture of DCs with aged CD4+ T cells resulted in increased production of IL-21 as compared to that with young CD4+ T cells. Further examination revealed that the response of aged naïve CD4+ T cells to IL-12 was altered, resulting in increased differentiation of aged Th cells towards Tfh cells. Investigation into the signaling mechanism suggested that phosphorylation of STAT-4 in response to IL-12 was sustained for a longer duration in aged CD4+ T cells as compared to CD4+ T cells from young subjects. Additional analysis demonstrated that increased IL-21 secretion correlated with chronic CMV infection in aged subjects. These findings indicate that chronic CMV infection alters the response of aged CD4+ T cells to IL-12 resulting in an increased secretion of IL-21 and that aging affects Tfh cell responses in humans which may contribute to age-associated inflammation and immune dysfunctions.