Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen

Abstract The mechanisms that guide Th2 cell differentiation in barrier tissues are unclear. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cells, we describe the molecular pathways driving allergen specific Th2 cells. Differentiation and migration of lung allergen-specific Th2 cells requires early expression of the transcriptional repressor Blimp-1. Loss of Blimp-1 during priming in the lymph node ablated the formation of Th2 cells that migrate to the lung, indicating early Blimp-1 promotes the population of Th2 cells with migratory capability. Blimp-1 occurs in a subset of lymph node CD4 T cells that requires IL-10 from allergen-specific T cells. Furthermore, IL-2/STAT5 signals are essential for both Blimp-1 and GATA3 upregulation through repression of Bcl6 and Bach2 in the lymph node. Spatial microniches of IL-2 in the lymph node identified by the latent factor discovery method SLIDE discriminate and support the earliest Blimp-1+ migratory Th2 cells, demonstrating that lymph node localization is a primary driver of Th2 initiation. Our findings illuminate the molecular pathways for inhaled allergens to promote Th2 cells and identify an early requirement for IL-2 mediated spatial microniches that synergize with allergen-driven IL-10 from responding T cells to drive allergic asthma