{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T10:37:42Z","timestamp":1769423862228,"version":"3.49.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR\u2212 and NCR+ ILC3 subsets in the small intestine of mice raised on a vitamin A\u2013deficient diet. Additionally, the percentages of IL-22\u2013producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR\u2212 ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A\u2013deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid\u2013related orphan receptor \u03b3t\u2013Cre \u00d7 RAR\u03b1-DN mice had reduced numbers of NCR\u2212 and NCR+ ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid\u2013related orphan receptor \u03b3t is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines.<\/jats:p>","DOI":"10.4049\/jimmunol.1501106","type":"journal-article","created":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T02:54:28Z","timestamp":1462848868000},"page":"5148-5155","source":"Crossref","is-referenced-by-count":77,"title":["Vitamin A Controls the Presence of ROR\u03b3+ Innate Lymphoid Cells and Lymphoid Tissue in the Small Intestine"],"prefix":"10.1093","volume":"196","author":[{"given":"Gera","family":"Goverse","sequence":"first","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center , 1081 BT Amsterdam ,","place":["the Netherlands"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7797-3797","authenticated-orcid":false,"given":"Carlos","family":"Labao-Almeida","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa , 1649-028 Lisbon ,","place":["Portugal"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-2400","authenticated-orcid":false,"given":"Manuela","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa , 1649-028 Lisbon ,","place":["Portugal"]}]},{"given":"Rosalie","family":"Molenaar","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center , 1081 BT Amsterdam ,","place":["the Netherlands"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2606-1023","authenticated-orcid":false,"given":"Sigrid","family":"Wahlen","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center , 1081 BT Amsterdam ,","place":["the Netherlands"]}]},{"given":"Tanja","family":"Konijn","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center , 1081 BT Amsterdam ,","place":["the Netherlands"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-4857","authenticated-orcid":false,"given":"Jasper","family":"Koning","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center , 1081 BT Amsterdam ,","place":["the Netherlands"]}]},{"given":"Henrique","family":"Veiga-Fernandes","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa , 1649-028 Lisbon ,","place":["Portugal"]}]},{"given":"Reina E","family":"Mebius","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, VU University Medical Center , 1081 BT Amsterdam ,","place":["the Netherlands"]}]}],"member":"286","published-online":{"date-parts":[[2016,6,15]]},"reference":[{"key":"2025030702180940800_r1","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1146\/annurev-immunol-020711-075053","article-title":"Innate lymphoid cells: emerging insights in development, lineage relationships, and function","volume":"30","author":"Spits","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"2025030702180940800_r2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.coi.2012.07.006","article-title":"Dietary and commensal derived nutrients: shaping mucosal and systemic immunity","volume":"24","author":"Spencer","year":"2012","journal-title":"Curr. Opin. Immunol."},{"key":"2025030702180940800_r3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nri3349","article-title":"Innate lymphoid cells\u2014how did we miss them?","volume":"13","author":"Walker","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"2025030702180940800_r4","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1002\/eji.201242639","article-title":"Transcriptional control of innate lymphoid cells","volume":"42","author":"Mj\u00f6sberg","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"2025030702180940800_r5","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/ni.1962","article-title":"The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling","volume":"12","author":"Spits","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030702180940800_r6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nri3365","article-title":"Innate lymphoid cells\u2014a proposal for uniform nomenclature","volume":"13","author":"Spits","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"2025030702180940800_r7","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.immuni.2010.10.017","article-title":"Regulated expression of nuclear receptor ROR\u03b3t confers distinct functional fates to NK cell receptor-expressing ROR\u03b3t+ innate lymphocytes","volume":"33","author":"Vonarbourg","year":"2010","journal-title":"Immunity"},{"key":"2025030702180940800_r8","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.coi.2013.02.010","article-title":"Development and function of group 2 innate lymphoid cells","volume":"25","author":"Walker","year":"2013","journal-title":"Curr. Opin. Immunol."},{"key":"2025030702180940800_r9","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S1074-7613(00)80371-4","article-title":"Developing lymph nodes collect CD4+CD3\u2212 LT\u03b2+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells","volume":"7","author":"Mebius","year":"1997","journal-title":"Immunity"},{"key":"2025030702180940800_r10","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nature07537","article-title":"A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity","volume":"457","author":"Cella","year":"2009","journal-title":"Nature"},{"key":"2025030702180940800_r11","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1126\/science.1214914","article-title":"Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles","volume":"334","author":"Kiss","year":"2011","journal-title":"Science"},{"key":"2025030702180940800_r12","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.immuni.2011.11.011","article-title":"The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells","volume":"36","author":"Qiu","year":"2012","journal-title":"Immunity"},{"key":"2025030702180940800_r13","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.immuni.2013.08.002","article-title":"Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora","volume":"39","author":"Qiu","year":"2013","journal-title":"Immunity"},{"key":"2025030702180940800_r14","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1084\/jem.20121588","article-title":"Retinoic acid expression associates with enhanced IL-22 production by \u03b3\u03b4 T cells and innate lymphoid cells and attenuation of intestinal inflammation","volume":"210","author":"Mielke","year":"2013","journal-title":"J. Exp. Med."},{"key":"2025030702180940800_r15","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1126\/science.1247606","article-title":"Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity","volume":"343","author":"Spencer","year":"2014","journal-title":"Science"},{"key":"2025030702180940800_r16","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature13158","article-title":"Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity","volume":"508","author":"van de Pavert","year":"2014","journal-title":"Nature"},{"key":"2025030702180940800_r17","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/415187a","article-title":"Co-regulator recruitment and the mechanism of retinoic acid receptor synergy","volume":"415","author":"Germain","year":"2002","journal-title":"Nature"},{"key":"2025030702180940800_r18","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.immuni.2004.08.011","article-title":"Retinoic acid imprints gut-homing specificity on T cells","volume":"21","author":"Iwata","year":"2004","journal-title":"Immunity"},{"key":"2025030702180940800_r19","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1242\/dev.127.8.1553","article-title":"Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches","volume":"127","author":"Wendling","year":"2000","journal-title":"Development"},{"key":"2025030702180940800_r20","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1126\/science.1096472","article-title":"Thymic origin of intestinal \u03b1\u03b2 T cells revealed by fate mapping of ROR\u03b3t+ cells","volume":"305","author":"Eberl","year":"2004","journal-title":"Science"},{"key":"2025030702180940800_r21","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1242\/dev.040287","article-title":"Non-cell-autonomous retinoid signaling is crucial for renal development","volume":"137","author":"Rosselot","year":"2010","journal-title":"Development"},{"key":"2025030702180940800_r22","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ni.2025","article-title":"Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22","volume":"12","author":"Sonnenberg","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030702180940800_r23","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.4049\/jimmunol.1001672","article-title":"Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A","volume":"186","author":"Molenaar","year":"2011","journal-title":"J. Immunol."},{"key":"2025030702180940800_r24","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/nri2832","article-title":"New insights into the development of lymphoid tissues","volume":"10","author":"van de Pavert","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025030702180940800_r25","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1084\/jem.184.4.1449","article-title":"Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop","volume":"184","author":"Kanamori","year":"1996","journal-title":"J. Exp. Med."},{"key":"2025030702180940800_r26","doi-asserted-by":"crossref","first-page":"6824","DOI":"10.4049\/jimmunol.177.10.6824","article-title":"Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling","volume":"177","author":"Pabst","year":"2006","journal-title":"J. Immunol."},{"key":"2025030702180940800_r27","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ydbio.2008.01.041","article-title":"Expression of the dominant negative retinoid receptor, RAR403, alters telencephalic progenitor proliferation, survival, and cell fate specification","volume":"316","author":"Rajaii","year":"2008","journal-title":"Dev. Biol."},{"key":"2025030702180940800_r28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/mi.2013.28","article-title":"Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid","volume":"7","author":"Martin","year":"2014","journal-title":"Mucosal Immunol."},{"key":"2025030702180940800_r29","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.str.2008.06.005","article-title":"Structure of IL-22 bound to its high-affinity IL-22R1 chain","volume":"16","author":"Jones","year":"2008","journal-title":"Structure"},{"key":"2025030702180940800_r30","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/mi.2013.60","article-title":"Lyn activity protects mice from DSS colitis and regulates the production of IL-22 from innate lymphoid cells","volume":"7","author":"Bishop","year":"2014","journal-title":"Mucosal Immunol."},{"key":"2025030702180940800_r31","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nature11535","article-title":"IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine","volume":"491","author":"Huber","year":"2012","journal-title":"Nature"},{"key":"2025030702180940800_r32","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1084\/jem.20122308","article-title":"Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model","volume":"210","author":"Kirchberger","year":"2013","journal-title":"J. Exp. Med."},{"key":"2025030702180940800_r33","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/mi.2012.61","article-title":"CX3CR1+ macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium","volume":"6","author":"Manta","year":"2013","journal-title":"Mucosal Immunol."},{"key":"2025030702180940800_r34","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1084\/jem.20140678","article-title":"CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22","volume":"211","author":"Longman","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030702180940800_r35","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/nature08949","article-title":"Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology","volume":"464","author":"Buonocore","year":"2010","journal-title":"Nature"},{"key":"2025030702180940800_r36","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1126\/science.1135245","article-title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene","volume":"314","author":"Duerr","year":"2006","journal-title":"Science"},{"key":"2025030702180940800_r37","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.4049\/jimmunol.1101494","article-title":"Cutting edge: a variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production","volume":"188","author":"Zwiers","year":"2012","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/196\/12\/5148\/62253108\/1501106.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/196\/12\/5148\/62253108\/1501106.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T02:42:53Z","timestamp":1741315373000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/196\/12\/5148\/7964220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6]]},"references-count":37,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,6,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1501106","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,6]]},"published":{"date-parts":[[2016,6]]}}}