Project description:Eosinophils contribute to parasitic helminths- and allergens-induced type 2 immune responses. Although the gastrointestinal tract harbors a substantial number of eosinophils, the pathophysiological roles of intestinal eosinophils remain unclear. Here we identify a novel subset of eosinophil that expresses a repertoire of inhibitory molecules, including Clec4a4 and PD-L1. These Clec4a4+ leukocytes are blood-derived and exclusively present in the small intestine. Accordingly, this subset acquires imprinted features by the instruction of AHR signaling, which modulates immune responses to establish gut homeostasis. Selective depletion of AHR in eosinophils leads to a marked reduction of Clec4a4+PD-L1+ eosinophils and enhances the worm clearance accompanied by an increased type 2 immune response. Our findings may open new therapeutic avenues on primary eosinophilic gastrointestinal disorders.
Project description:Intestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes, including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil residence in the gut remains unclear. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.
Project description:To determine how AHR affects eosinophil adaptation to the intestinal environment, eosinophils were sorted from the small intestine from WT, Ahr knockout and Ahrr knockout mice and compared by RNA sequencing. The canonical AHR pathway was active in murine intestinal eosinophils and limited eosinophil survival in the small intestine in a cell-intrinsic manner. Eosinophils from AHR-deficient mice retained increased expression of pathways associated with bone marrow eosinophils and failed to fully express the intestinal gene expression program, including extracellular matrix organization and cell junction pathways. Thus, our study demonstrates that the response to environmental triggers via AHR shapes tissue adaptation of eosinophils in the small intestine.
Project description:Objective: To study the physiological role of eosinophils in the GI tract and lung under homeostatic conditions, Method: we analyzed tissue-specific eosinophil gene expression patterns by genome-wide expression microarray analysis using RNA isolated from FACS-sorted eosinophils from the small intestine or lung of naive BALB/cmice (Live eosinophils were identified as DAPI-CCR3+Siglec-F+CD45+CD4-CD8a-CD19-B220-SSChigh cells). Result: There are 513 genes that are differentially expressed by intestinal eosinophils and Lung eosinophils. Conclusion: Eosinophils from different tissues have unique gene expression patterns for distinct functions. we analyzed tissue-specific eosinophil gene expression patterns by genome-wide expression microarray analysis using RNA isolated from FACS-sorted eosinophils from the small intestine or lung of naive BALB/cmice (Live eosinophils were identified as DAPI-CCR3+Siglec-F+CD45+CD4-CD8a-CD19-B220-SSChigh cells).
Project description:To determine how eosinophils adapt to the intestinal environment, eosinophils were sorted from the bone marrow and small intestine and compared by RNA sequencing. We show here that intestinal eosinophils were specifically adapted to their environment and underwent substantial transcriptomic changes. Intestinal eosinophils upregulated genes relating to the immune response and cell-cell communication, extracellular matrix components and metalloproteases, and the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with broad functions in intestinal homeostasis.
Project description:Eosinophils are commonly regarded as effector cells of type 2 immunity, yet they also accumulate in certain tissues during homeostasis - particularly in the gastrointestinal tract. Our understanding of the processes that govern homeostatic eosinophil accumulation and tissue-specific adaptation, and their functional significance, remains very limited. Here, we investigated how eosinophils adapt to the small intestine microenvironment and the local signals that regulate this process. We observed that eosinophils gradually migrate up the crypt-villus axis, giving rise to a villus-resident subpopulation with a distinct transcriptional signature. Genetic deficiency of eosinophils resulted in a reduction of villus area, as well as a reduction of multiple other immune cell populations, demonstrating their diverse functions in this environment. We determined that retinoic acid receptor signaling is specifically required for the maintenance of villus-resident eosinophils, while IL-5 is largely dispensable outside of its canonical role in eosinophil production. In addition, we unexpectedly found that high protein diet suppresses the accumulation of villus-resident eosinophils. Purified amino acids were sufficient for this effect, which was a consequence of accelerated eosinophil turnover within the tissue microenvironment and not due to altered development in the bone marrow. Our study provides new insight into the process of eosinophil adaptation to the small intestine and its dependence on nutrient-derived signals.