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TLR activated APC enhance the response of aged naïve CD4 T cells via an IL‐6 dependent mechanism

Toll like receptor (TLR) ligands hold great potential as adjuvants to enhance the aged antigen specific CD4 T cell response. We established an in vitro model to determine whether TLR ligand stimulated bone marrow derived dendritic cells were capable of enhancing the response of aged naïve CD4 T cells. Antigen presentation by non‐stimulated bone marrow derived dendritic cells (BMDCs) results in an aged naïve influenza‐specific Tg CD4 T cell response characterized by reduced expansion, reduced IL‐2 production, and increased cell death of activated cells. Upon stimulation with TLR ligands BMDCs express higher levels of CD80, CD40 and MHC class II, and secrete increased amounts of TNFα, RANTES, IL‐12p70, IL‐12p40, IL‐6 and KC. Aged Tg naïve CD4 T cells activated by TLR ligand stimulated BMDCs exhibited enhanced expansion and reduced cell death that correlated with the increased expression of the anti‐apoptotic molecule, Bcl‐2. Analysis of culture supernatants revealed an early increase in the levels of IL‐2, IL‐6 and KC when aged cells were activated by TLR ligand treated BMDCs. The addition of anti‐IL‐6 blocking antibodies at the initiation of the culture completely prevented the rescue of the aged response, indicating that inflammatory cytokines are a central component to enhancing the aged CD4 T cell response. We feel that these are exciting data that clearly establish a mechanism for how TLR ligands may serve as adjuvants for enhancing the function of aged CD4 T cells.