Memory CD4+ T helper type 2 (Th2) cells drive allergic asthma, yet the mechanisms whereby tissue-resident memory Th2 (Th2 Trm) cells and circulating memory Th2 cells collaborate in vivo remain unclear. Using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm cells and circulating memory Th2 cells perform nonredundant functions. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+ T cell recruitment. In contrast, Th2 Trm cells proliferated near airways and induced mucus metaplasia, airway hyperresponsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm cells and circulating memory Th2 cells share a core Th2 gene signature but also exhibit distinct transcriptional profiles. Th2 Trm cells express a tissue-adaptation signature, including genes involved in regulating and interacting with extracellular matrix. Our findings demonstrate that Th2 Trm cells and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.

Foxp3 + regulatory T (T reg ) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether T reg cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2 + T reg cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2 + T reg cells were activated by IL-33 to suppress IL-17-producing γδ T cells. ST2 signaling in T reg cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for T reg cell-mediated suppression of γδ T cells. This response resulted in less eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing inflammation induced by allergen. Thus, we define a fundamental role for ST2 + T reg cells in the lung as a negative regulator of the early innate γδ T cell response to mucosal injury.

50 Memory CD4 + T helper type 2 (Th2) cells are critical in driving allergic asthma 51 pathogenesis, yet the mechanisms whereby tissue-resident memory Th2 cells (Th2 Trm) 52 and circulating memory Th2 cells collaborate in vivo remain unclear. Here, using a 53 house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that 54 Th2 Trm and circulating memory Th2 cells perform non-redundant functions in vivo. 55 Upon HDM re-challenge, circulating memory Th2 cells trafficked into the lung 56 parenchyma and ignited perivascular inflammation to promote eosinophil and CD4 + T 57 cell recruitment. In contrast, Th2 Trm proliferated near airways and promoted mucus 58 metaplasia, airway hyper-responsiveness, and airway eosinophil activation. 59