Spatial microniches of IL-2 combine with IL-10 to drive lung migratory TH2 cells in response to inhaled allergen

Abstract

The mechanisms that guide T helper 2 (T_H2) cell differentiation in barrier tissues are unclear. Here we describe the molecular pathways driving allergen-specific T_H2 cells using temporal, spatial and single-cell transcriptomic tracking of house dust mite-specific T cells in mice. Differentiation and migration of lung allergen-specific T_H2 cells requires early expression of the transcriptional repressor Blimp-1. Loss of Blimp-1 during priming in the lymph node ablated the formation of T_H2 cells in the lung, indicating early Blimp-1 promotes T_H2 cells with migratory capability. IL-2/STAT5 signals and autocrine/paracrine IL-10 from house dust mite-specific T cells were essential for Blimp-1 and subsequent GATA3 upregulation through repression of Bcl6 and Bach2. Spatial microniches of IL-2 in the lymph node supported the earliest Blimp-1⁺T_H2 cells, demonstrating lymph node localization is a driver of T_H2 initiation. Our findings identify an early requirement for IL-2-mediated spatial microniches that integrate with allergen-driven IL-10 from responding T cells to drive allergic asthma.