{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T10:44:05Z","timestamp":1788173045493,"version":"build-2803163510"},"posted":{"date-parts":[[2026,3,7]]},"group-title":"Immunology","reference-count":23,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T00:00:00Z","timestamp":1772841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by impaired central immune tolerance due to deficiency of the Autoimmune Regulator (AIRE) and is characterized by severe, multiorgan autoimmunity. We recently identified interferon-\u03b3 (IFN-\u03b3) as a dominant driver of immunopathology in APECED and showed that treatment with the JAK1\/2 inhibitor ruxolitinib ameliorates disease in both AIRE-deficient mice and patients. However, broad JAK inhibition is associated with clinically relevant toxicities, raising the question of whether selective targeting of individual JAK pathways can retain efficacy while sparing nonpathogenic immune programs. Here, we systematically evaluated the effects of selective JAK1, JAK2, and JAK3 inhibition in\n                  <jats:italic>Air<\/jats:italic>\n                  e\n                  <jats:sup>\u2212\/\u2212<\/jats:sup>\n                  mice. Selective JAK1 and JAK2 inhibition reduced autoimmune tissue injury, suppressed IFN-\u03b3 signaling, and decreased accumulation of pathogenic T cells, with JAK2 inhibition providing the most robust protection, comparable to ruxolitinib. In contrast, selective JAK3 inhibition decreased T cell accumulation, but paradoxically increased the proportion of IFN-\u03b3-producing T cells and did not significantly attenuate IFN-\u03b3-driven tissue inflammation. These findings reveal an unexpected uncoupling between lymphocyte burden and pathogenic cytokine bias and identify IFN-\u03b3 signaling as hierarchically dominant over \u03b3c-dependent pathways in AIRE deficiency. Together, our data indicate that effective control of APECED-associated autoimmunity requires direct suppression of the IFN-\u03b3-JAK2 axis rather than generalized lymphocyte inhibition and suggest that selective JAK2 targeting may represent a rational strategy to preserve therapeutic efficacy while minimizing disruption of JAK1-and \u03b3c-dependent immune functions.\n                <\/jats:p>","DOI":"10.64898\/2026.03.05.709894","type":"posted-content","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T04:20:19Z","timestamp":1772943619000},"source":"Crossref","is-referenced-by-count":1,"title":["Selective JAK Inhibition Reveals Paradoxical and Hierarchical Control of interferon-\u03b3-driven Autoimmunity in AIRE Deficiency"],"prefix":"10.64898","author":[{"given":"Eliezer","family":"Heller","sequence":"first","affiliation":[{"name":"Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"dos Santos Dias","sequence":"additional","affiliation":[{"name":"Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4994-9500","authenticated-orcid":false,"given":"Michail S.","family":"Lionakis","sequence":"additional","affiliation":[{"name":"Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026031104250744000_2026.03.05.709894v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-399"},{"issue":"765","key":"2026031104250744000_2026.03.05.709894v1.2","doi-asserted-by":"crossref","first-page":"eadk0845","DOI":"10.1126\/scitranslmed.adk0845","article-title":"A deep intronic splice-altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion","volume":"16","year":"2024","journal-title":"Sci Transl Med"},{"key":"2026031104250744000_2026.03.05.709894v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.021"},{"key":"2026031104250744000_2026.03.05.709894v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199006283222601"},{"key":"2026031104250744000_2026.03.05.709894v1.5","unstructured":"Ferre, E.M. , et al., Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. JCI Insight, 2016. 1(13)."},{"key":"2026031104250744000_2026.03.05.709894v1.6","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa140"},{"key":"2026031104250744000_2026.03.05.709894v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2009.02090.x"},{"key":"2026031104250744000_2026.03.05.709894v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075958"},{"key":"2026031104250744000_2026.03.05.709894v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.07.005"},{"key":"2026031104250744000_2026.03.05.709894v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-015-0176-y"},{"key":"2026031104250744000_2026.03.05.709894v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-393"},{"key":"2026031104250744000_2026.03.05.709894v1.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2312665"},{"key":"2026031104250744000_2026.03.05.709894v1.13","unstructured":"Break, T.J. , et al., Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science, 2021. 371(6526)."},{"key":"2026031104250744000_2026.03.05.709894v1.14","doi-asserted-by":"crossref","unstructured":"Dai, Z. , et al., Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata. JCI Insight, 2021. 6(7).","DOI":"10.1172\/jci.insight.142205"},{"key":"2026031104250744000_2026.03.05.709894v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-10777-w"},{"issue":"11","key":"2026031104250744000_2026.03.05.709894v1.16","doi-asserted-by":"crossref","first-page":"703","DOI":"10.2217\/fon-2023-0964","article-title":"Anemia-related response end points in myelofibrosis clinical trials: current trends and need for renewed consensus","volume":"20","year":"2024","journal-title":"Future Oncol"},{"key":"2026031104250744000_2026.03.05.709894v1.17","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050693"},{"key":"2026031104250744000_2026.03.05.709894v1.18","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25194"},{"key":"2026031104250744000_2026.03.05.709894v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.005"},{"key":"2026031104250744000_2026.03.05.709894v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-021-00726-8"},{"issue":"4","key":"2026031104250744000_2026.03.05.709894v1.21","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/j.1460-2075.1996.tb00415.x","article-title":"Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state","volume":"15","year":"1996","journal-title":"Embo j"},{"key":"2026031104250744000_2026.03.05.709894v1.22","doi-asserted-by":"crossref","unstructured":"Shao, S. , et al., IFN-gamma enhances cell-mediated cytotoxicity against keratinocytes via JAK2\/STAT1 in lichen planus. Sci Transl Med, 2019. 11(511).","DOI":"10.1126\/scitranslmed.aav7561"},{"key":"2026031104250744000_2026.03.05.709894v1.23","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12714"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.05.709894","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T11:25:16Z","timestamp":1773228316000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.05.709894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,7]]},"references-count":23,"URL":"https:\/\/doi.org\/10.64898\/2026.03.05.709894","relation":{},"subject":[],"published":{"date-parts":[[2026,3,7]]},"subtype":"preprint"}}