Noncanonical NF-κB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development

Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on both T-cell intrinsic factors and the supporting function of B cells, but the underlying molecular mechanisms are incompletely understood. Here we show that NF-kappa B-inducing kinase (NIK), a central component of the noncanonical NF-kappa B signaling pathway, is required for Tfh cell development. Unlike other known Tfh regulators, NIK acts by controlling the supporting function of B cells. NIK and its upstream BAFF receptor regulate B-cell expression of inducible costimulator ligand (ICOSL), a molecule required for Tfh cell generation. Consistently, injection of a recombinant ICOSL protein into NIK-deficient mice largely rescues their defect in Tfh cell development. We provide biochemical and genetic evidence indicating that the ICOSL gene is a specific target of the noncanonical NF-kappa B. Our findings suggest that the noncanonical NF-kappa B pathway regulates the development of Tfh cells by mediating ICOSL gene expression in B cells.