TNF promotes Th17 vaccine responses by enabling myeloid cell pattern recognition via Mincle

Abstract Successful induction of protective T cells by subunit vaccines requires adjuvants. The adjuvant CAF01 potently induces robust Th17 responses that depend on the C-type lectin receptor Mincle and TNF. Mincle expression is low in resting macrophages, but upregulated by TNF. Here, we used conditional TNFR1-deficient mice to dissect cell type-specific contributions of TNF signaling to Th17 induction by the recombinant tuberculosis fusion protein H1 adjuvanted with CAF01. TNFR1 in myeloid cells was essential, whereas TNFR1 deletion in DC only partially reduced Th17 cells, and TNFR1 was not required in T cells. Constitutive, TNF-independent transgenic Mincle expression restored Th17 induction despite TNF blockade. Thus, regulation of Mincle by TNF plays a causal role, likely by controlling production of Th17-polarizing cytokines in monocytes. Together, we show that induction of Th17 by CAF01 requires TNF signaling in myeloid cells, with enhanced adjuvant sensing due to Mincle upregulation as a potential mechanism.