PROJECT SUMMARY – Regulation of Allergic inflammation by IL-9-secreting T cells Interleukin-9 (IL-9) is a pleuripotent cytokine that leads to altered gene expression and cellular function in hematopoietic and structural cell populations. IL-9 is most efficiently produced by innate lymphoid cells, and a specialized subset of T helper cells termed Th9 cells. Importantly, IL-9 has a role, in both humans and mouse models, in asthma, food allergy, ulcerative colitis, and anti-tumor immunity. In the previous funding period of this grant we have made considerable progress in understanding the regulation of the Il9 gene and the transcription factors that are involved in controlling Il9 gene expression. As we defined systems for best analyzing IL-9-secreting T cells in vivo, we observed that in a model of chronic allergen exposure, IL-9- producing CD4+ T cells were in the tissue resident memory (Trm) population. We further observed that the IL- 9-secreting Trm population was stable in the absence of allergen exposure and was instrumental in mediating the inflammatory response to allergen challenge after a period of ‘rest’ from allergen exposure. Blocking IL-9 during this post-rest challenge significantly diminished the inflammatory response. In this renewal application, we will define the identity of the IL-9-secreting T cells, determine the transcription factors that are required for their development, and identify the cytokines that are important for their development, maintenance, and effector function. As the CD4+ Trm population in allergic inflammation has not been characterized and this population is likely important in the context of intermittent allergen exposure as occurs in seasonal allergies, the proposed studies could have a foundational impact on understanding how CD4+ Trm impact allergic disease.