Interleukin-4-producing type 2 innate lymphoid cells in the lymph node promote proallergic Tfh13 cell differentiation.

Abstract

Proallergic T follicular helper 13 (Tfh13) cells are obligatory for generating high-affinity, anaphylactic immunoglobulin E (IgE) responses to allergens. Unlike Tfh2 cells, which are induced by vaccination and most type 2 immune responses, Tfh13 cells are primarily elicited during allergic disease states. However, the cellular and molecular determinants governing Tfh13 cell differentiation remain unclear. Using orthogonal genetic and bone marrow chimera approaches, we identified a critical role for group 2 innate lymphoid cells (ILC2s) within draining lymph nodes (dLNs) in promoting Tfh13 cell differentiation. During allergen sensitization, ILC2s trafficked into dLNs in a chemokine receptor CCR8-dependent manner and produced interleukin (IL)-4, a factor necessary for Tfh13-but not for Tfh2-cell induction. These findings uncover a mechanism by which ILC2s selectively drive pathogenic Tfh13 responses, underscoring the distinct regulatory requirements for Tfh2 and Tfh13 cell differentiation in allergic immunity.