TY - JOUR
T1 - The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4+ eosinophils unique to the small intestine
AU - Wang, Wei Le
AU - Kasamatsu, Jun
AU - Joshita, Satoru
AU - Gilfillan, Susan
AU - Luccia, Blanda Di
AU - Panda, Santosh K.
AU - Kim, Do Hyun
AU - Desai, Pritesh
AU - Bando, Jennifer K.
AU - Huang, Stanley Ching Cheng
AU - Yomogida, Kentaro
AU - Hoshino, Hitomi
AU - Fukushima, Mana
AU - Jacobsen, Elizabeth A.
AU - Van Dyken, Steven J.
AU - Ruedl, Christiane
AU - Cella, Marina
AU - Colonna, Marco
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Prof. Motohiro Kobayashi for advice and helpful discussions, Hong-Erh Liang and Richard Locksley for the gift of N. brasiliensis larvae, Ken Murphy and Arifumi Iwata for providing lung eosinophils from house dust mite–treated mice, the Hope Center Animal Surgery Core for performing parabiosis experiments, and the Genome Technology Access Center (GTAC) in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. GTAC is partially supported by National Cancer Institute Cancer Center Support Grant P30 CA91842 (to the Siteman Cancer Center) and National Center for Research Resources Institute of Clinical and Translational Sciences/Clinical and Translational Science Awards Grant UL1 TR000448. J.K. is supported by The Naito Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi Sankyo Foundation of Life Science grants for studying overseas. S.J. is supported by the Promotion Project of Education, Research, and Medical Care from Shinshu
Funding Information:
University Hospital. The generation of Clec4a4 reporter mice was supported by Mucosal Immunology Studies Team NIH Grant AI095542.
Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/6/7
Y1 - 2022/6/7
N2 - C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α2 conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a42 eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.
AB - C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α2 conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a42 eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.
KW - allergy
KW - aryl hydrocarbon receptor
KW - eosinophil
KW - helminth
KW - intestine
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U2 - 10.1073/pnas.2204557119
DO - 10.1073/pnas.2204557119
M3 - Article
C2 - 35653568
AN - SCOPUS:85131257024
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
M1 - e2204557119
ER -