The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4⁺eosinophils unique to the small intestine

Abstract

Significance Eosinophils contribute to type 2 immunity against helminths and allergens. The small intestine harbors eosinophils with incompletely understood pathophysiological roles. Here, we show that intestinal eosinophils include two subsets. One expresses the inhibitory receptor Clec4a4 and the inhibitory ligand PD-L1 and is unique to the small intestine; the other manifests a proinflammatory phenotype. Both subsets are blood derived. Remarkably, Clec4a4 + eosinophils were instructed by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that imprints many gut immune cells. Selective AHR deletion in eosinophils depleted Clec4a4 + eosinophils, augmented innate lymphocytes producing type 2 cytokines, and enhanced helminth clearance. We conclude that Clec4a4 + eosinophils have immunomodulatory functions, which could be harnessed for the therapy of food allergies and eosinophilic gastrointestinal disorders.

Neuromedin U programs eosinophils to promote mucosal immunity of the small intestine

“…1B). SI eosinophils were further characterized by high expression of many genes involved in cholesterol biosynthesis (e.g., Hmgcs1 and Sc5d ), which corroborates a recent study highlighting de novo cholesterol biosynthesis in SI eosinophils ( 11 ) and G protein–coupled receptor signaling pathways for homomers and neurotransmitters. We further ranked the tissue-specific genes (Fig.…”

“…However, eosinophils are particularly abundant in the small intestine (SI) under homeostatic conditions ( 3 , 4 ), where they regulate multiple physiological processes ( 5 – 7 ). SI eosinophils exhibit distinctive surface proteins, transcriptional states, and signs of degranulation ( 8 – 11 ), which suggests that they undergo a tissue adaptation process in the SI. However, the tissue-derived cues that regulate eosinophil responses in the SI remain poorly understood.…”

Eosinophils from A to Z

“…348 Interestingly, AHR was reported to drive the expression of immunomodulatory features such as the C-type lectin domain family 4, member a4 (Clec4a4)-a C-type lectin inhibitory receptor-and the inhibitory ligand programmed death-ligand 1 (PD-L1) in a distinct subset of blood-derived mouse eosinophils exclusively found in the lamina propria of the small intestine. 217 Moreover, different mouse eosinophil subsets were categorized as progenitors, steady state eosinophils, and type 1 and 2 activated phenotypes implying that different tissue microenvironments shape eosinophil phenotype and function. 349 In accordance, a recent study identified five eosinophil subpopulations including eosinophil precursors, immature, circulating, basal, and active eosinophils across mouse tissues based on single-cell transcriptomic profiling.…”

“…Interestingly, it has been demonstrated that the transcription factor aryl hydrocarbon receptor (AHR) partially controls the transcriptomic changes in the process of tissue adaption of mouse intestinal eosinophils 348 . Interestingly, AHR was reported to drive the expression of immunomodulatory features such as the C‐type lectin domain family 4, member a4 (Clec4a4)—a C‐type lectin inhibitory receptor—and the inhibitory ligand programmed death‐ligand 1 (PD‐L1) in a distinct subset of blood‐derived mouse eosinophils exclusively found in the lamina propria of the small intestine 217 . Moreover, different mouse eosinophil subsets were categorized as progenitors , steady state eosinophils, and type 1 and 2 activated phenotypes implying that different tissue microenvironments shape eosinophil phenotype and function 349 .…”

Granulocyte development, tissue recruitment, and function during allergic inflammation

“…A subset of eosinophils with immunomodulatory functions was recently identified in the small intestine lamina propria of naïve mice. This population increases during aging and expresses the aryl hydrocarbon receptor and PD-L1, a ligand of the inhibitory receptor PD-1 expressed on T cells and other cell types [64,65]. In line, another recent study described a CD80 and PD-L1 expressing eosinophil population with the potential to suppress T cells that was increased during inflammatory bowel disease in mice and in a small cohort of human patients (eosinophils were defined in human as MBP + PD-L1 + cells).…”