P2X receptor agonist enhances tumor-specific CTL responses through CD70+ DC-mediated Th17 induction

Extracellular ATP is known to promote T(h)17 cell differentiation in the intestinal lamina propria by stimulating CD70(+)CD11c(low) dendritic cells (DCs) via P2X receptors (P2XRs). Recent studies have also shown that T(h)17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, alpha beta-methylene ATP (alpha beta-ATP), as a mucosal vaccine adjuvant to promote CTL responses through T(h)17 induction. We demonstrated that (i) CD70(+)CD11c(low) DCs were present in the nasal lamina propria and expressed P2X1R, P2X2R and P2X4R; (ii) CD70(+)CD11c(low) DCs isolated from the nasal lamina propria enhanced T(h)17 cell differentiation of cocultured splenic CD4(+) T cells upon stimulation with alpha beta-ATP; (iii) mice intranasally immunized with ovalbumin (OVA) and alpha beta-ATP had increased OVA-specific T(h)17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (iv) mice intranasally immunized with OVA and alpha beta-ATP also had elevated resistance to E.G7-OVA tumor growth compared with those intranasally immunized with OVA alone; (v) suramin, a broad-range inhibitor of P2 receptors, suppressed the increases of OVA-specific T(h)17 cells and CTLs in mice intranasally immunized with OVA and alpha beta-ATP; and (vi) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and alpha beta-ATP against E.G7-OVA. Collectively, alpha beta-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70(+)CD11c(low) DC-mediated T(h)17 induction.