{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:27:25Z","timestamp":1793330845135,"version":"4.5.0"},"reference-count":41,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,29]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction and impaired regulatory T-cell (Treg) function, yet its molecular basis remains poorly defined. Here, we show that CD4+ naive T cells from patients with ITP exhibit diminished T-cell receptor (TCR) signaling and impaired in vitro Treg induction relative to healthy controls. RNA sequencing revealed widespread dysregulation of alternative splicing, most notably exon 8 skipping in LCK, a kinase central to TCR signaling and Treg differentiation. Using an LCK minigene combined with RNA pull-down mass spectrometry and RNA immunoprecipitation assays, we identified the splicing factor SRSF1 as a direct upstream regulator of LCK exon 8 skipping. Notably, SRSF1 expression was reduced in CD4+ naive T cells from patients with ITP, and its overexpression restored in vitro Treg induction capacity. Antisense oligonucleotide\u2013mediated blockade of SRSF1 binding to LCK enhanced exon 8 skipping and attenuated TCR activation in Jurkat cells. Although murine Lck lacks the human-specific recursive splicing sites required for exon 8 exclusion, the adoptive transfer of CD4+ naive T cells expressing the exon 8\u2013skipped murine Lck into CD61-knockout mice significantly reduced Treg proportions and platelet counts in an active ITP model. Mechanistically, Jurkat cells engineered to express only the exon 8\u2013skipped LCK variant showed markedly reduced binding to ZAP70 and CD3\u03b6, which may partly account for the attenuated TCR signaling and downstream FOXP3 induction. Together, these findings define a novel SRSF1-LCK splicing axis that may regulate Treg development in ITP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2026033543","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:24:14Z","timestamp":1786987454000},"page":"2239-2250","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Reduced SRSF1 expression correlates with\n                    <i>LCK<\/i>\n                    exon skipping and impaired Treg induction in immune thrombocytopenia"],"prefix":"10.1182","volume":"148","author":[{"given":"Xiang","family":"Hu","sequence":"first","affiliation":[{"name":"1Shandong Key Laboratory of Hematological Diseases and Immune Microenvironment, Qilu Hospital of Shandong University, Jinan, China"},{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoqiu","family":"Leng","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxia","family":"Zhao","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Liu","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Li","sequence":"additional","affiliation":[{"name":"3Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyun","family":"Meng","sequence":"additional","affiliation":[{"name":"4Department of Blood Transfusion, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Liu","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Wang","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Feng","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Jiang","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqian","family":"Xu","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"},{"name":"5Shandong Provincial Clinical Research Center for Hematological Diseases, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Wang","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"},{"name":"6State Key Laboratory for Innovation and Transformation of Luobing Theory, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1434-1490","authenticated-orcid":false,"given":"Jun","family":"Peng","sequence":"additional","affiliation":[{"name":"1Shandong Key Laboratory of Hematological Diseases and Immune Microenvironment, Qilu Hospital of Shandong University, Jinan, China"},{"name":"2Department of Hematology, Qilu Hospital of Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"6","key":"2026102911214810600_bib1","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.autrev.2017.04.012","article-title":"Pathogenesis of immune thrombocytopenia","volume":"16","author":"Audia","year":"2017","journal-title":"Autoimmun Rev"},{"issue":"12","key":"2026102911214810600_bib2","doi-asserted-by":"crossref","first-page":"103677","DOI":"10.1016\/j.autrev.2024.103677","article-title":"Autoimmune effector mechanisms associated with a defective immunosuppressive axis in immune thrombocytopenia (ITP)","volume":"23","author":"Li","year":"2024","journal-title":"Autoimmun Rev"},{"issue":"13","key":"2026102911214810600_bib3","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1056\/NEJMra010501","article-title":"Immune thrombocytopenic purpura","volume":"346","author":"Cines","year":"2002","journal-title":"N Engl J Med"},{"issue":"12","key":"2026102911214810600_bib4","doi-asserted-by":"crossref","first-page":"e153580","DOI":"10.1172\/JCI153580","article-title":"High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura","volume":"132","author":"Canales-Herrerias","year":"2022","journal-title":"J Clin Invest"},{"issue":"1","key":"2026102911214810600_bib5","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1182\/blood.V98.1.130","article-title":"Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura","volume":"98","author":"Kuwana","year":"2001","journal-title":"Blood"},{"issue":"7","key":"2026102911214810600_bib6","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1172\/JCI4238","article-title":"Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody","volume":"102","author":"Kuwana","year":"1998","journal-title":"J Clin Invest"},{"issue":"7","key":"2026102911214810600_bib7","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41577-024-00994-x","article-title":"The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases","volume":"24","author":"Sumida","year":"2024","journal-title":"Nat Rev Immunol"},{"issue":"7","key":"2026102911214810600_bib8","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41590-018-0120-4","article-title":"Regulatory T cells in autoimmune disease","volume":"19","author":"Dominguez-Villar","year":"2018","journal-title":"Nat Immunol"},{"issue":"2","key":"2026102911214810600_bib9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.24272\/j.issn.2095-8137.2021.363","article-title":"Engineered T cells and their therapeutic applications in autoimmune diseases","volume":"43","author":"Bao","year":"2022","journal-title":"Zool Res"},{"issue":"3","key":"2026102911214810600_bib10","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s00281-019-00741-8","article-title":"Treg cells in autoimmunity: from identification to Treg-based therapies","volume":"41","author":"G\u00f6schl","year":"2019","journal-title":"Semin Immunopathol"},{"issue":"1","key":"2026102911214810600_bib11","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41577-018-0083-6","article-title":"Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation","volume":"19","author":"Klein","year":"2019","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"2026102911214810600_bib12","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1084\/jem.20110308","article-title":"T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse","volume":"208","author":"Moran","year":"2011","journal-title":"J Exp Med"},{"issue":"8","key":"2026102911214810600_bib13","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1084\/jem.20091999","article-title":"TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo","volume":"207","author":"Gottschalk","year":"2010","journal-title":"J Exp Med"},{"issue":"7","key":"2026102911214810600_bib14","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/s41590-018-0131-1","article-title":"Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT","volume":"19","author":"Lo","year":"2018","journal-title":"Nat Immunol"},{"issue":"2","key":"2026102911214810600_bib15","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.molcel.2019.09.017","article-title":"Alternative splicing regulatory networks: functions, mechanisms, and evolution","volume":"76","author":"Ule","year":"2019","journal-title":"Mol Cell"},{"key":"2026102911214810600_bib16","doi-asserted-by":"crossref","first-page":"713540","DOI":"10.3389\/fimmu.2021.713540","article-title":"Alternative splicing: a new cause and potential therapeutic target in autoimmune disease","volume":"12","author":"Ren","year":"2021","journal-title":"Front Immunol"},{"issue":"7822","key":"2026102911214810600_bib17","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41586-020-2436-0","article-title":"FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease","volume":"584","author":"Saevarsdottir","year":"2020","journal-title":"Nature"},{"issue":"2","key":"2026102911214810600_bib18","doi-asserted-by":"crossref","first-page":"350","DOI":"10.2337\/db21-0194","article-title":"Genetic control of splicing at SIRPG modulates risk of type 1 diabetes","volume":"71","author":"Smith","year":"2022","journal-title":"Diabetes"},{"issue":"22","key":"2026102911214810600_bib19","doi-asserted-by":"crossref","first-page":"3780","DOI":"10.1182\/bloodadvances.2019000812","article-title":"Updated international consensus report on the investigation and management of primary immune thrombocytopenia","volume":"3","author":"Provan","year":"2019","journal-title":"Blood Adv"},{"issue":"51","key":"2026102911214810600_bib20","doi-asserted-by":"crossref","first-page":"E5593","DOI":"10.1073\/pnas.1419161111","article-title":"rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-seq data","volume":"111","author":"Shen","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"2026102911214810600_bib21","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1016\/j.cell.2021.04.012","article-title":"Dynamic imaging of nascent RNA reveals general principles of transcription dynamics and stochastic splice site selection","volume":"184","author":"Wan","year":"2021","journal-title":"Cell"},{"issue":"6","key":"2026102911214810600_bib22","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1182\/blood-2009-09-244772","article-title":"A murine model of severe immune thrombocytopenia is induced by antibody\u2212 and CD8+ T cell-mediated responses that are differentially sensitive to therapy","volume":"115","author":"Chow","year":"2010","journal-title":"Blood"},{"issue":"4","key":"2026102911214810600_bib23","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nri.2016.26","article-title":"T cell receptor signalling in the control of regulatory T cell differentiation and function","volume":"16","author":"Li","year":"2016","journal-title":"Nat Rev Immunol"},{"issue":"12","key":"2026102911214810600_bib24","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1084\/jem.20030152","article-title":"Conversion of peripheral CD4+CD25\u2212 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3","volume":"198","author":"Chen","year":"2003","journal-title":"J Exp Med"},{"issue":"8","key":"2026102911214810600_bib25","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1182\/blood.2020008477","article-title":"Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia","volume":"138","author":"Han","year":"2021","journal-title":"Blood"},{"issue":"4","key":"2026102911214810600_bib26","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.3390\/ijms22041678","article-title":"The GAUGAA motif is responsible for the binding between circSMARCA5 and SRSF1 and related downstream effects on glioblastoma multiforme cell migration and angiogenic potential","volume":"22","author":"Barbagallo","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"7552","key":"2026102911214810600_bib27","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nature14466","article-title":"Recursive splicing in long vertebrate genes","volume":"521","author":"Sibley","year":"2015","journal-title":"Nature"},{"issue":"11","key":"2026102911214810600_bib28","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nri1485","article-title":"Regulatory T cells: friend or foe in immunity to infection?","volume":"4","author":"Mills","year":"2004","journal-title":"Nat Rev Immunol"},{"issue":"5955","key":"2026102911214810600_bib29","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1126\/science.1172702","article-title":"CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner","volume":"326","author":"Chaudhry","year":"2009","journal-title":"Science"},{"issue":"103","key":"2026102911214810600_bib30","doi-asserted-by":"crossref","first-page":"eads6295","DOI":"10.1126\/sciimmunol.ads6295","article-title":"Functional differences between rodent and human PD-1 linked to evolutionary divergence","volume":"10","author":"Masubuchi","year":"2025","journal-title":"Sci Immunol"},{"issue":"7","key":"2026102911214810600_bib31","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.4049\/jimmunol.0904028","article-title":"Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells","volume":"184","author":"Thornton","year":"2010","journal-title":"J Immunol"},{"issue":"10","key":"2026102911214810600_bib32","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1084\/jem.20120914","article-title":"Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells","volume":"209","author":"Weiss","year":"2012","journal-title":"J Exp Med"},{"issue":"10","key":"2026102911214810600_bib33","doi-asserted-by":"crossref","first-page":"e0141161","DOI":"10.1371\/journal.pone.0141161","article-title":"Differences in expression level of Helios and neuropilin-1 do not distinguish thymus-derived from extrathymically-induced CD4+Foxp3+ regulatory T cells","volume":"10","author":"Szurek","year":"2015","journal-title":"PLoS One"},{"key":"2026102911214810600_bib34","doi-asserted-by":"crossref","first-page":"276","DOI":"10.3389\/fimmu.2016.00276","article-title":"Helios should not be cited as a marker of human thymus-derived Tregs. Commentary: Helios(+) and Helios(-) cells coexist within the natural FOXP3(+) T regulatory cell subset in humans","volume":"7","author":"Elkord","year":"2016","journal-title":"Front Immunol"},{"issue":"6721","key":"2026102911214810600_bib35","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1126\/science.adn8105","article-title":"Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome","volume":"386","author":"Rogalska","year":"2024","journal-title":"Science"},{"issue":"1","key":"2026102911214810600_bib36","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.molcel.2010.09.013","article-title":"Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing","volume":"40","author":"Heyd","year":"2010","journal-title":"Mol Cell"},{"issue":"5889","key":"2026102911214810600_bib37","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1126\/science.1157610","article-title":"Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL","volume":"321","author":"Oberdoerffer","year":"2008","journal-title":"Science"},{"issue":"6714","key":"2026102911214810600_bib38","doi-asserted-by":"crossref","first-page":"eadj1979","DOI":"10.1126\/science.adj1979","article-title":"Autoregulated splicing of TRA2\u03b2 programs T cell fate in response to antigen-receptor stimulation","volume":"385","author":"Karginov","year":"2024","journal-title":"Science"},{"issue":"7","key":"2026102911214810600_bib39","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1074\/jbc.M113.518662","article-title":"Ubiquitination regulates expression of the serine\/arginine-rich splicing factor 1 (SRSF1) in normal and systemic lupus erythematosus (SLE) T cells","volume":"289","author":"Moulton","year":"2014","journal-title":"J Biol Chem"},{"key":"2026102911214810600_bib40","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.thromres.2020.04.004","article-title":"Dexamethasone suppresses the Th17\/1 cell polarization in the CD4+ T cells from patients with primary immune thrombocytopenia","volume":"190","author":"Li","year":"2020","journal-title":"Thromb Res"},{"issue":"26","key":"2026102911214810600_bib41","doi-asserted-by":"crossref","first-page":"6511","DOI":"10.1182\/blood-2009-01-129155","article-title":"The ITP syndrome: pathogenic and clinical diversity","volume":"113","author":"Cines","year":"2009","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/148\/18\/2239\/2597019\/blood_bld-2026-033543-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/148\/18\/2239\/2597019\/blood_bld-2026-033543-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:21:58Z","timestamp":1793287318000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/148\/18\/2239\/570176\/Reduced-SRSF1-expression-correlates-with-LCK-exon"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,29]]},"references-count":41,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,10,29]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2026033543","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10,29]]},"published":{"date-parts":[[2026,10,29]]}}}