Autocrine pro-inflammatory IL-10 initiates lung-specific Th2 responses to inhaled allergen to induce allergic asthma

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Abstract Allergic asthma remains a significant health burden for both children and adults. CD4 +Th2 cells are critical drivers of disease, yet the mechanisms that support initiation of the Th2 cell response to environmental allergens are not well understood. We demonstrated a distinct requirement for the transcriptional repressor Blimp-1 to promote Th2 cells in the lung to inhaled but not systemically or subcutaneously delivered allergens. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cell responses, we demonstrate that inhalation of HDM drove early Blimp-1 expression necessary for GATA3 upregulation and subsequent Th2 differentiation in the lung that coincides with IL2Rα expression. Blimp-1 expression remains confined to HDM-specific Treg and Th2 cells that traffic to the lung but importantly is dispensable for Th2 cell maintenance. We found that inhaled allergens induce a pattern of STAT activation with transient pSTAT5 concomitant with sustained pSTAT3 within GATA3 +allergen-specific T cells, which is critical for the induction of Blimp-1 during the earliest phase of T cell priming in the lymph node. IL2Rα cooperates with IL10Rα signaling acting directly on allergen specific T cells to drive Th2 cell differentiation. Furthermore, IL-10 derived from allergen specific T cells was sufficient to induce Th2 cells suggesting an autocrine or paracrine loop of IL-10 supports Blimp-1 to regulate GATA3 upregulation at the T-B border and subsequent Th2 differentiation. These data shed light on the steps initiating Th2 responses to inhaled allergens and identify an unexpected pro-inflammatory requirement for IL-10 and Blimp-1 driving inflammatory T cell responses to environmental antigens.