TLR2 engagement primes for expansive effector and memory CD4 T cells through early effects on DC activation

Ligation of Toll like receptors (TLR) during the early stages of infection by pathogen-associated motifs (PAMPs) provides critical costimulatory signals for the initiation of adaptive immune responses. Individual TLR have distinct PAMP specificities, with TLR4 recognizing lipopolysaccharide (LPS) and TLR2 binding bacterial lipopeptides. The use of non-infectious synthetic TLR agonists as vaccine adjuvants is a promising approach to generate pathogen-specific adaptive responses. However, the ability of specific TLR engagement to promote primary and secondary immune responses remains unresolved.;We investigated how TLR2 engagement in vivo influenced CD4 T cell priming and memory generation, compared to the well-characterized TLR4 agonist LPS. We hypothesize that TLR2 engagement will alter quantitative and functional characteristics of activated CD4 T cells that will influence long-term memory generation. We demonstrate that antigen-specific CD4 T cells undergo rapid and expansive proliferation in the presence of peptide and TLR agonist, with TLR2 priming resulting in higher expansion compared to TLR4 priming. In addition, TLR2-primed CD4 T cells produced predominantly IL-2 and IL-17 in contrast to TLR4-primed CD4 T cells consisting of IFN-g and IL-2 producers. The ability of TLR2 agonist to differentially prime CD4 T cells was due to its engagement on APC, as wild type (WT) antigen-specific CD4 T cells in TLR2-deficient hosts lost the ability to expand to peptide stimulation in vivo or produce IL-2 in vitro upon peptide recall.;Moreover, TLR2 agonist priming of influenza hemagglutinin (HA)-specific CD4 T cells resulted in a higher frequency of persisting HA-specific memory CD4 T cells compared to TLR4 agonist primed cells. TLR2 primed flu-specific CD4 T cells also accumulated at higher levels at the site of infection and mediated increased infiltration of polymorphonuclear cells into the lung following influenza challenge. Our findings demonstrate that TLR2 priming via early engagement of APC promotes expansive effector and memory CD4 T cells in primary and secondary immune responses, with implications for promoting T cell differentiation in vaccines and to pathogens in vivo.