The response of aged CD4 T cells to vaccines is less than that of young T cells resulting in ineffectiveness of many current vaccines and contributing to the greater susceptibility of the aged to new infections. We find that activation of DC by TLR ligands (*DC), used as APC for naive CD4 T cells, induces their production of high levels of IL-6 that improve aged CD4 T expansion, cytokine production and survival. Importantly, this enhances their ability to differentiate into T follicular helper cells that promote long-term B cell responses and sustained antibody production, a key to vaccine-induced immunity. The enhanced helper function of aged CD4 T cells is lost if the *DC cannot make IL-6, while effects of *DC on young CD4 T cells are not IL-6 dependent. This suggests that loss of responsiveness to IL-6 is central to the aged defects of CD4 T cells. We find that in vitro IL-6 signaling of the aged is blunted such that the dose of IL-6 required to achieve a particular level of IL-6R internalization and phosphorylation of STAT3 is higher in the aged vs. young naïve CD4 T cells. Clearly, the ability of aged CD4 T cells to respond to the strong *DC-mediated IL-6 signal during their interaction is still intact and can restore their function to that comparable to young cells. This *DC-based vaccine strategy to localize pro-inflammatory cytokines to the Ag-specific CD4 T cells, also avoids counterproductive and often-dangerous bystander effects of adjuvants given systemically.
- Copyright © 2013 by The American Association of Immunologists, Inc.