{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T08:28:54Z","timestamp":1790497734164,"version":"4.1.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell development. Abnormal MHC II expression can lead to immunodeficiency, clinically termed as type II bare lymphocyte syndrome (BLS), which usually results from mutations in the MHC II transactivator (CIITA) and other coactivators. Here, we present a new paradigm for MHC II deficiency in mice that involves a spontaneous point mutation on H2-Aa. A significantly reduced population of CD4<jats:sup>+<\/jats:sup> T cells was observed in mice obtained from the long-term homozygous breeding of <jats:italic>autophagy-related gene microtubule-associated protein 1 light chain 3 \u03b2<\/jats:italic> (Map1<jats:italic>lc3b<\/jats:italic>, <jats:italic>Lc3b<\/jats:italic>) knockout mice; this phenotype was not attributed to the original knocked-out gene. MHC II expression was generally reduced, together with a marked deficiency of H2-Aa in the immune cells of these mice. Using cDNA and DNA sequencing, a spontaneous H2-Aa point mutation that led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift was identified in these mice. These findings led to the discovery of a new type of spontaneous MHC II deficiency and provided a new paradigm to explain type II BLS in mice.<\/jats:p>","DOI":"10.3389\/fimmu.2022.810824","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T07:04:48Z","timestamp":1646377488000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["A Spontaneous H2-Aa Point Mutation Impairs MHC II Synthesis and CD4+ T-Cell Development in Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Yun","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Xia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Na","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-Fang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Min","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Hao","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.humimm.2018.07.004","article-title":"Role of Membrane Environment and Membrane-Spanning Protein Regions in Assembly and Function of the Class II Major Histocompatibility Complex","volume":"80","author":"Dixon","year":"2019","journal-title":"Hum Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3818","article-title":"The Ins and Outs of MHC Class II-Mediated Antigen Processing and Presentation","volume":"15","author":"Roche","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nri3084","article-title":"Towards a Systems Understanding of MHC Class I and MHC Class II Antigen Presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.09.002","article-title":"An Alternate Pathway for CD4 T Cell Development: Thymocyte-Expressed MHC Class II Selects a Distinct T Cell Population","volume":"23","author":"Li","year":"2005","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/nri1708","article-title":"Regulation of MHC Class II Gene Expression by the Class II Transactivator","volume":"5","author":"Reith","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.331","article-title":"The Bare Lymphocyte Syndrome and the Regulation of MHC Expression","volume":"19","author":"Reith","year":"2001","journal-title":"Annu Rev Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nri1257","article-title":"T-Cell Development Made Simple","volume":"4","author":"Zuniga-Pflucker","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.07.010","article-title":"The Mechanisms of T Cell Selection in the Thymus","volume":"38","author":"Takaba","year":"2017","journal-title":"Trends Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2006.07.007","article-title":"Epigenetic Regulation of MHC-II and CIITA Genes","volume":"27","author":"Wright","year":"2006","journal-title":"Trends Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00696-7","article-title":"Genetic Control of MHC Class II Expression","author":"Ting","year":"2002","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/icb.2014.81","article-title":"Autophagy in T-Cell Development, Activation and Differentiation","volume":"93","author":"Bronietzki","year":"2015","journal-title":"Immunol Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1084\/jem.20061303","article-title":"A Critical Role for the Autophagy Gene Atg5 in T Cell Survival and Proliferation","volume":"204","author":"Pua","year":"2007","journal-title":"J Exp Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501190102","article-title":"Autophagy Promotes MHC Class II Presentation of Peptides From Intracellular Source Proteins","volume":"102","author":"Dengjel","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B14","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.immuni.2006.10.018","article-title":"Antigen-Loading Compartments for Major Histocompatibility Complex Class II Molecules Continuously Receive Input From Autophagosomes","volume":"26","author":"Schmid","year":"2007","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104904","article-title":"Endogenous MHC Class II Processing of a Viral Nuclear Antigen After Autophagy","volume":"307","author":"Paludan","year":"2005","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110640","article-title":"Autophagy in Antigen-Presenting Cells Results in Presentation of Citrullinated Peptides to CD4 T Cells","volume":"208","author":"Ireland","year":"2011","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1874209","article-title":"Autophagy Restricts Mitochondrial DNA Damage-Induced Release of ENDOG (Endonuclease G) to Regulate Genome Stability","volume":"17","author":"Chao","year":"2021","journal-title":"Autophagy"},{"key":"B18","doi-asserted-by":"publisher","first-page":"5692958","DOI":"10.1155\/2019\/5692958","article-title":"Autophagy: A Player in Response to Oxidative Stress and DNA Damage","volume":"2019","author":"Galati","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.jaut.2015.12.004","article-title":"Sonic Hedgehog Regulates Thymic Epithelial Cell Differentiation","volume":"68","author":"Saldana","year":"2016","journal-title":"J Autoimmun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1376161","article-title":"MTOR Signaling is Essential for the Development of Thymic Epithelial Cells and the Induction of Central Immune Tolerance","volume":"14","author":"Liang","year":"2018","journal-title":"Autophagy"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ni1171","article-title":"A Cytosolic Pathway for MHC Class II-Restricted Antigen Processing That is Proteasome and TAP Dependent","volume":"6","author":"Tewari","year":"2005","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2010.45","article-title":"Association of the 19S Proteasomal ATPases With the ATPase-Binding Domain of CIITA Is Essential for CIITA Stability and MHC Class II Expression","volume":"88","author":"Bhat","year":"2010","journal-title":"Immunol Cell Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900579","article-title":"The MHC Haplotype H2b Converts Two Pure Nonlupus Mouse Strains to Producers of Antinuclear Antibodies","volume":"183","author":"Hannestad","year":"2009","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.3.1787","article-title":"Mutation in the Class II Trans-Activator Leading to a Mild Immunodeficiency","volume":"167","author":"Wiszniewski","year":"2001","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.tig.2018.10.002","article-title":"And Disease: Animal Models to Therapies","volume":"35","author":"Montes","year":"2019","journal-title":"Trends Genet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.810824\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T07:04:51Z","timestamp":1646377491000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.810824\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":25,"alternative-id":["10.3389\/fimmu.2022.810824"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.810824","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,4]]},"article-number":"810824"}}