Progressively differentiated TFH13 cells are stabilized by JunB to mediate allergen germinal center responses

Abstract

Allergic diseases are common and affect a large proportion of the population. Interleukin-13 (IL-13)-expressing follicular helper T (T_FH13) cells are a newly identified population of T_FH cells that have been associated with high-affinity IgE responses. However, the origins, developmental signals, transcriptional programming and precise functions of T_FH13 cells are unknown. Here, we examined the developmental signals for T_FH13 cells and found a direct and progressive differentiation pathway marked by the production of IL-21. These two pathways differed in kinetics and extrinsic requirements. However, both pathways converged, forming transcriptionally similar T_FH13 cells that express the transcription factor JunB as a critical stabilizing factor. Using an intersectional genetics-based T_FH13-diphtheria toxin receptor model to perturb these cells, we found that T_FH13 cells were essential to drive broad germinal center responses and allergen-specific IgG and IgE. Moreover, we found that IL-21 is a broad positive regulator of allergen germinal center B cells and synergizes with IL-13 produced by T_FH13 cells to amplify allergic responses. Thus, T_FH13 cells orchestrate multiple features of allergic inflammation.