{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:02:15Z","timestamp":1785438135691,"version":"3.56.0"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"28","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["AR077007"],"award-info":[{"award-number":["AR077007"]}]},{"name":"NIH","award":["AR080392"],"award-info":[{"award-number":["AR080392"]}]},{"name":"NIH","award":["AR080392"],"award-info":[{"award-number":["AR080392"]}]},{"name":"NIH","award":["AI167047"],"award-info":[{"award-number":["AI167047"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,14]]},"abstract":"<jats:p>\n                    Cutaneous allergen sensitization (CAS) is a primary driver of atopic dermatitis (AD) and a key initiator of the \u201catopic march\u201d, which can lead to systemic conditions such as food allergy and anaphylaxis. The type 2 cytokine interleukin-13 (IL-13) is an important regulator of high-affinity IgE antibodies, yet the precise cellular targets and mechanisms by which it orchestrates systemic allergic responses remain incompletely understood. Here, we evaluated the role of IL-13 in a murine CAS model that links skin inflammation to systemic anaphylaxis. Using cell-specific deletions of the IL-13 receptor \u03b11 subunit (\n                    <jats:italic toggle=\"yes\">Il13ra1<\/jats:italic>\n                    ), we identify conventional dendritic cells (cDCs), and not T or B cells, as the essential targets of IL-13 for generating high-affinity IgE. Single-cell transcriptomics reveal that IL-13 signaling acts specifically in a cDC2 subset characterized by high expression of CX3CR1, Clec10a (CD301a), and CD301b (Mgl2). Licensing by IL-13 endows these cDC2 with superior antigen-presenting capacity, characterized by the upregulation of MHC class II and costimulatory molecules, including CD301a, CD301b, and ICOSL. These mature cDC2s are mobilized from the periphery to the spleen by a CX3CR1-dependent mechanism, where they are uniquely equipped to induce the differentiation of IL-13-producing T follicular helper (T\n                    <jats:sub>FH<\/jats:sub>\n                    13) cells. This cascade results in robust germinal center reactions and production of pathogenic, high-affinity IgE. Our findings define an IL-13\u2013cDC2 axis that functions as a critical regulator of the atopic march, providing a mechanistic rationale for the clinical efficacy of IL-13-targeted therapies in allergic diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2608478123","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T17:57:37Z","timestamp":1783619857000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["IL-13 signaling in cDC2 is required for systemic anaphylactic responses"],"prefix":"10.1073","volume":"123","author":[{"given":"Yasuyo","family":"Harada","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05sj3n476","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Molecular Pathology, Tokyo University of Science","place":["Noda-shi, Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Sasaki","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05sj3n476","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Molecular Pathology, Tokyo University of Science","place":["Noda-shi, Chiba, Japan"]},{"name":"Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine","place":["Shinjuku-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazushige","family":"Obata-Ninomiya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04j9rp686","id-type":"ROR","asserted-by":"publisher"}],"name":"Benaroya Research Institute, Center for Fundamental 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Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshie","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory for Cytokine Regulation, Center for Integrative Medical Science, RIKEN Yokohama Institute","place":["Tsurumi, Yokohama, Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ito","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05sj3n476","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Immunology and Allergy, Research Institute for Biomedical Science, Tokyo University of Science","place":["Noda-shi, Chiba, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutaka","family":"Motomura","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05sj3n476","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Immunology and Allergy, Research Institute for Biomedical Science, Tokyo University of 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Harada , Type 2 helper T cells convert into Interleukin-13-expressing follicular helper T cells after antigen repriming. Transl. Regul. Sci. 5, 1\u201312 (2023).","journal-title":"Transl. Regul. Sci."},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.11.020"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000029"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01067-0"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.01.011"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3244"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","unstructured":"U. Gowthaman J. S. Chen S. C. Eisenbarth Regulation of IgE by T follicular helper cells. J. Leukoc. Biol.107 409\u2013418 (2020).","DOI":"10.1002\/JLB.3RI1219-425R"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2011.09.041"},{"key":"e_1_3_4_23_2","unstructured":"Y. Harada T. Sasaki S. Shichino S. Ueha W. Bin Single-cell RNA-seq of murine dendritic cells in presence or absence of Il13ra1. GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE227209. Deposited 13 March 2023."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","unstructured":"C. C. Brown . Transcriptional basis of mouse and human dendritic cell heterogeneity. Cell 179 846-863.e24 (2019).","DOI":"10.1016\/j.cell.2019.09.035"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","unstructured":"C. M. Minutti . Distinct ontogenetic lineages dictate cDC2 heterogeneity. Nat. Immunol. 25 448\u2013461 (2024).","DOI":"10.1038\/s41590-024-01745-9"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","unstructured":"R. Leylek Integrated cross-species analysis identifies a conserved transitional dendritic cell population. 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Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation. J. Immunol. 157 607\u2013616 (1996).","DOI":"10.4049\/jimmunol.157.2.607"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","unstructured":"E. Sallmann . High-affinity IgE receptors on dendritic cells exacerbate Th2-dependent inflammation. J. Immunol. 187 164\u2013171 (2011).","DOI":"10.4049\/jimmunol.1003392"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","unstructured":"B. Platzer M. Stout E. Fiebiger Functions of dendritic-cell-bound IgE in allergy. Mol. Immunol. 68 116\u2013119 (2015).","DOI":"10.1016\/j.molimm.2015.05.016"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4573"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","unstructured":"P. F. Rodrigues . Progenitors of distinct lineages shape the diversity of mature type 2 conventional dendritic cells. Immunity 57 1567-1585.e5 (2024).","DOI":"10.1016\/j.immuni.2024.05.007"},{"key":"e_1_3_4_37_2","first-page":"5259","article-title":"The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed lymphatics","volume":"126","author":"Johnson L. A.","year":"2013","unstructured":"L. A. Johnson, D. G. Jackson, The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed lymphatics. J. Cell Sci. 126, 5259\u20135270 (2013).","journal-title":"J. Cell Sci."},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","unstructured":"F. Shen . Novel small-molecule CX3CR1 antagonist impairs metastatic seeding and colonization of breast cancer cells. Mol. 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Dobin STARsolo: Accurate fast and versatile mapping\/quantification of single-cell and single-nucleus RNA-seq data. bioRxiv [Preprint] (2021). https:\/\/doi.org\/10.1101\/2021.05.05.442755.","DOI":"10.1101\/2021.05.05.442755"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05083-x"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1662-y"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.271908.120"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"e_1_3_4_67_2","doi-asserted-by":"crossref","unstructured":"Y. Hao Integrated analysis of multimodal single-cell data. 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