Eosinophils are resident immune cells of the healthy gastrointestinal (GI) tract. Once considered exclusively inflammatory cells that support allergic (Th2) inflammation, recent evidence demonstrates a role for eosinophils in supporting a more broad set of inflammatory responses and in the maintenance of metabolic homeostasis. Indeed, eosinophils are a component of both active and inactive lesions in inflammatory bowel disease (IBD). Although eosinophils become activated upon entry into tissues, the factors controlling their homeostasis and the consequences of eosinophil activation in the GI tract remain enigmatic. The GI tract and associated lymphoid tissues (GALT) are in apposition with commensal flora, food protein and environmental antigen. These factors act on multiple innate immune cell populations in the GI tissue including antigen presenting cells, which prime adaptive immune responses, and resident accessory cells which shape the outcome of these responses at tissue sites. Eosinophils are a prominent population of resident cells within lamina propria of the small and large intestine. However, the function of these resident cells and how they are regulated by the dominant signals present in the gut: the commensal microbiota and the dietary metabolites, is unclear. Our preliminary data suggest that commensal microbiota and the essential dietary nutrient, Vitamin A, strongly influence eosinophil activation and survival respectively. Sensing of dietary and microbial cues in the gut by resident innate cells is key to priming and sustaining CD4+ T effector responses (Teff) secreting IFN-3 (Th1) and/or IL-17 (Th17). Accordingly, our preliminary data using the eosinophil deficient dblGATA mouse model, demonstrate that the absence of eosinophils results in impaired ability to mount Teff responses in the gut. The overarching goal of this application is to 1) define the role of commensal bacteria and dietary components in controlling GI eosinophil function and homeostasis and 2) define the mechanisms by which eosinophils are regulating effector immune responses in the GI tract. Better understanding GI eosinophils will help expand knowledge of their pathogenic role in IBD. These studies will elucidate novel pathways of eosinophils in contributing to Teff responses in the GI tract and may provide novel therapeutic targets to both prevent pathology in IBD, but also to promote beneficial immunity in the context of mucosal vaccines.
The proposed studies will revolve around the eosinophil, which is an enigmatic and poorly understood cell type. Although commonly associated with allergy and asthma, we believe the eosinophil may have diverse roles outside of allergic inflammation. Through these studies we will understand the role of the eosinophil in promoting vaccine-induced immunity in the intestine.
|Kotzin, Jonathan J; Spencer, Sean P; McCright, Sam J et al. (2016) The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature 537:239-243|
|Spencer, S P; Wilhelm, C; Yang, Q et al. (2014) Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343:432-7|
|Yagi, Ryoji; Zhong, Chao; Northrup, Daniel L et al. (2014) The transcription factor GATA3 is critical for the development of all IL-7RÎ±-expressing innate lymphoid cells. Immunity 40:378-88|
|Korn, L L; Thomas, H L; Hubbeling, H G et al. (2014) Conventional CD4+ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol 7:1045-57|
|Mortha, Arthur; Chudnovskiy, Aleksey; Hashimoto, Daigo et al. (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288|
|Klebanoff, Christopher A; Spencer, Sean P; Torabi-Parizi, Parizad et al. (2013) Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells. J Exp Med 210:1961-76|
|Spencer, Sean P; Belkaid, Yasmine (2012) Dietary and commensal derived nutrients: shaping mucosal and systemic immunity. Curr Opin Immunol 24:379-84|
|SciumÃ©, Giuseppe; Hirahara, Kiyoshi; Takahashi, Hayato et al. (2012) Distinct requirements for T-bet in gut innate lymphoid cells. J Exp Med 209:2331-8|
|Naik, Shruti; Bouladoux, Nicolas; Wilhelm, Christoph et al. (2012) Compartmentalized control of skin immunity by resident commensals. Science 337:1115-9|