{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T02:21:03Z","timestamp":1787451663115,"version":"build-2736575974"},"reference-count":127,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Sciences and Engineering Research Council","award":["RGPIN-2020-20705"],"award-info":[{"award-number":["RGPIN-2020-20705"]}]},{"name":"Canadian Foundation for Innovation","award":["30017"],"award-info":[{"award-number":["30017"]}]},{"name":"National Sciences and Engineering Research Council, and from the Faculty of Medicine of the Universit\u00e9 de Montr\u00e9al"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The invariant chain (Ii) trimerizes in the endoplasmic reticulum and swiftly associates with nascent alpha and beta chains of major histocompatibility complex class II (MHCII) molecules. Ii was ascribed many roles pertaining to the antigen presentation capacity of MHCII molecules. The lack of Ii in knockout mice revealed its isotype- and cell type\u2013dependent impact over the folding and trafficking of MHCII molecules. In humans, the role of Ii was mainly assessed in transfected cells. Here, using the CRISPR-Cas9 system, we addressed the impact of inactivating the Ii genes on the expression and functions of MHCII molecules in human B cell lines. Our results revealed that the absence of Ii had very little impact, at least quantitatively, on the surface display of multiple HLA-DR and HLA-DP allotypes. However, Ii had a strong influence on the folding of the many HLA-DQ allotypes expressed in Raji and LG2 cells. Both the p33 and p35 isoforms of Ii could independently restore HLA-DQ expression at the plasma membrane. The loss of Ii did not prevent the presentation of the HA307\u2013318 peptide from the inactivated influenza X31 virus, in line with the fact that this epitope is loaded onto recycling HLA-DR molecules. We also found that Ii reduces the expression of LFA-1, a function that is most likely related to the ability of its cytoplasmic domain to act as a transcriptional regulator. Finally, using a biotin ligation assay in vivo, we identified Ii-dependent proximity partners of the HLA-DR\u03b2 cytoplasmic tail. Altogether, these results highlighted the pleiotropic functions of Ii in humans and uncovered new actors involved in the antigen presentation function of MHCII molecules.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag201","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T23:58:54Z","timestamp":1787443134000},"source":"Crossref","is-referenced-by-count":0,"title":["Invariant chain controls HLA-DQ folding and shapes the HLA class II proxiome"],"prefix":"10.1093","volume":"215","author":[{"given":"Mohamed Abdelwafi","family":"Moulefera","sequence":"first","affiliation":[{"name":"Laboratoire d\u2019Immunologie Mol\u00e9culaire, D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Institut Courtois d\u2019Innovation Biom\u00e9dicale (CI2B), Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2687-6905","authenticated-orcid":false,"given":"William","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Immunologie Mol\u00e9culaire, D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Institut Courtois d\u2019Innovation Biom\u00e9dicale (CI2B), Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"El Bilali","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pathologie et Biologie Cellulaire, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Centre de Recherche du CHU Sainte-Justine , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelilah","family":"Majdoubi","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Immunologie Mol\u00e9culaire, D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Institut Courtois d\u2019Innovation Biom\u00e9dicale (CI2B), Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Pan\u00e8s","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Institut de Recherche en Immunologie et Canc\u00e9rologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Salti","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Centre de Recherche du Centre Hospitalier Universitaire de l\u2019Universit\u00e9 de Montr\u00e9al, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Lipp\u00e9","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pathologie et Biologie Cellulaire, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Centre de Recherche du CHU Sainte-Justine , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9tienne","family":"Gagnon","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Institut de Recherche en Immunologie et Canc\u00e9rologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Mourad","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Centre de Recherche du Centre Hospitalier Universitaire de l\u2019Universit\u00e9 de Montr\u00e9al, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0790-9634","authenticated-orcid":false,"given":"Jacques","family":"Thibodeau","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Immunologie Mol\u00e9culaire, D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]},{"name":"Institut Courtois d\u2019Innovation Biom\u00e9dicale (CI2B), Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"2026082221314476900_vkag201-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4889(01)00166-5","article-title":"Multiple roles of the invariant Chain in MHC class II function","volume":"1542","author":"Stumptner-Cuvelette","year":"2002","journal-title":"Biochim Biophys Acta"},{"key":"2026082221314476900_vkag201-B2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0161-5890(79)90027-0","article-title":"Detection of a Common polypeptide Chain in I-A and I-E sub-region 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An alternatively spliced exon encodes a cysteine-rich domain highly homologous to a repetitive sequence of thyroglobulin","volume":"6","author":"Koch","year":"1987","journal-title":"Embo J"},{"key":"2026082221314476900_vkag201-B12","doi-asserted-by":"crossref","first-page":"3478","DOI":"10.4049\/jimmunol.148.11.3478","article-title":"Assembly and transport properties of invariant chain trimers and HLA-DR-invariant chain complexes","volume":"148","author":"Lamb","year":"1992","journal-title":"J Immunol"},{"key":"2026082221314476900_vkag201-B13","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.4049\/jimmunol.163.10.5435","article-title":"Phosphorylation of the invariant chain by protein kinase C regulates MHC class II trafficking to antigen-processing compartments","volume":"163","author":"Anderson","year":"1999","journal-title":"J 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reticulum","volume":"13","author":"Schutze","year":"1994","journal-title":"Embo J"},{"key":"2026082221314476900_vkag201-B17","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1073\/pnas.95.3.1056","article-title":"Exit of major histocompatibility complex class II-invariant chain p35 complexes from the endoplasmic reticulum is modulated by phosphorylation","volume":"95","author":"Kuwana","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026082221314476900_vkag201-B18","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.humimm.2015.02.002","article-title":"ER egress of invariant chain isoform p35 requires direct binding to MHCII molecules and is inhibited by the NleA virulence factor of enterohaemorrhagic Escherichia coli","volume":"76","author":"Cloutier","year":"2015","journal-title":"Hum Immunol"},{"key":"2026082221314476900_vkag201-B19","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1084\/jem.164.5.1490","article-title":"Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain","volume":"164","author":"Sekaly","year":"1986","journal-title":"J Exp Med"},{"key":"2026082221314476900_vkag201-B20","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1084\/jem.164.5.1478","article-title":"Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain","volume":"164","author":"Miller","year":"1986","journal-title":"J Exp Med"},{"key":"2026082221314476900_vkag201-B21","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1073\/pnas.88.6.2346","article-title":"Invariant chain promotes egress of poorly expressed, haplotype-mismatched class II major histocompatibility complex AaBb dimers from the endoplasmic reticulum\/cis-Golgi compartment","volume":"88","author":"Layet","year":"1991","journal-title":"Proc Natl Acad Sci 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class II peptide binding and expression","volume":"207","author":"Busch","year":"2005","journal-title":"Immunol Rev"},{"key":"2026082221314476900_vkag201-B37","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/1074-7613(94)90049-3","article-title":"Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells","volume":"1","author":"Denzin","year":"1994","journal-title":"Immunity"},{"key":"2026082221314476900_vkag201-B38","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.bbamcr.2016.03.026","article-title":"The multifaceted roles of the invariant chain CD74\u2014More than just a chaperone","volume":"1863","author":"Schroder","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2026082221314476900_vkag201-B39","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1750-1326-4-41","article-title":"CD74 interacts with APP and suppresses the production of 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