Defining the functions of tissue-resident and circulating memory Th2 cells in allergic asthma
Rod A. Rahimi1,2,3, Keshav Nepal1,2,4, Murat Cetinbas5,6, Ruslan I. Sadreyev5,7, and Andrew D. Luster1,2,4
1Airway Immunity Research Program, 2Center for Immunology and Inflammatory Diseases, 3Division of Pulmonary and Critical Care Medicine, 4Division of Rheumatology, Allergy, and Immunology, 5Department of Molecular Biology, 6Department of Genetics, 7Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
Tissue-resident memory T (Trm) cells are a unique population of memory T cells that are durably parked in non-lymphoid tissues and play an important role in host defense against recurrent infection and malignancy. CD4+ T helper type 2 (Th2) cells play a central role in allergic diseases, including asthma, but the biology of Th2 Trm cells in recurrent allergic inflammation is not well defined. Specifically, the mechanisms whereby Th2 Trm cells and circulating memory Th2 cells promote allergic asthma pathogenesis 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 distinct functions in vivo. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote inflammatory cell recruitment, including CD4+ T cells, eosinophils, and dendritic cells. In contrast, Th2 Trm cells proliferated near airways and were critical in promoting 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 extracellular matrix biology and lipid metabolism. Our findings demonstrate that Th2 Trm cells and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in vivo, with the establishment of Th2 Trm cells being critical for the full manifestation of allergic airway disease. Defining the unique mechanisms regulating the development and maintenance of Th2 Trm cells within the lungs has the potential to yield novel therapeutic approaches for allergic asthma.