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Engagement of TLR2 during priming directs enhanced CD4 T cell expansion and protective capacities compared to other TLR agonists

Toll‐like receptors (TLR) comprise a family of pattern recognition receptors that recognize pathogen‐associated motifs, and trigger antigen‐presenting cell (APC) activation for priming CD4 T cells. We hypothesized that CD4 T cell responses could be optimized by targeting engagement of specific TLR during priming. We used an in vivo system in which HA‐specific or OVA‐specific CD4 T cells are CFSE labeled, adoptively transferred into BALB/c hosts, and subsequently primed with antigenic peptide in the presence/absence of agonists for TLR2 (Pam3Cys), TLR3 (polyI:C) or TLR4 (lipopolysaccharide). CD4 T cells were harvested 1–2 weeks post‐priming to monitor expansion, functional capacity and protective responses against PR8 Influenza challenge. Transferred CD4 T cells underwent robust antigen‐driven proliferation and expansion when primed with both peptide and TLR agonist compared to peptide alone. Pam3Cys‐mediated priming resulted in significantly expanded populations with high levels of IFN‐γ and IL‐2 production, whereas TLR3 and TLR4 engagement resulted in predominant IFN‐γ production with low IL‐2 production. When challenged with a sub‐lethal dose of Influenza virus, Pam3Cys‐primed CD4 T cells afforded better protection in terms of lung function and viral load compared to TLR3 and TLR4 agonists. Thus targeting TLR2 during early priming leads to enhanced CD4 T cell activation, function and protection.