Water-in-Oil–Only Adjuvants Selectively Promote T Follicular Helper Cell Polarization through a Type I IFN and IL-6–Dependent Pathway

T follicular helper (Tfh) cells are a subset of CD4 + T lymphocytes that promote the development of humoral immunity. Although the triggers required for the differentiation of the other major Th subsets are well defined, those responsible for Tfh cell responses are still poorly understood. We determined that mice immunized with peptide or protein Ags emulsified in IFA or related water-in-oil adjuvants develop a highly polarized response in which the majority of the Ag-specific CD4 + T cells are germinal center-homing CXCR5 + Bcl6 + Tfh cells. Despite the absence of exogenous microbial pathogen-associated molecular patterns, the Tfh cell responses observed were dependent, in part, on MyD88. Importantly, in addition to IL-6, T cell-intrinsic type I IFN signaling is required for optimal Tfh cell polarization. These findings suggest that water-in-oil adjuvants promote Tfh cell-dominated responses by triggering endogenous alarm signals that, in turn, induce type I IFN-dependent differentiation pathway functioning in T cells.