{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T15:44:33Z","timestamp":1784735073239,"version":"3.55.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"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":[[2019,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Foxp3+T regulatory cells (Tregs) control autoimmune response by suppressing proliferation and effector functions of self-reactive Foxp3\u2212CD4+\/CD8+ T cells and thereby maintain the critical balance between self-tolerance and autoimmunity. Earlier, we had shown that OX40L-JAG1 cosignaling mediated through their cognate receptors OX40 and Notch3 preferentially expressed on murine Tregs can selectively induce their proliferation in the absence of TCR stimulation. However, the differential molecular mechanisms regulating TCR-independent versus TCR-dependent Treg proliferation and lineage stability of the expanded Tregs remained unknown. In this study, we show that OX40L-JAG1 treatment induced TCR-independent proliferation of Tregs in the thymus and periphery. The use of Src kinase inhibitor permitted us to demonstrate selective inhibition of TCR-dependent T cell proliferation with little to no effect on OX40L-JAG1\u2013induced TCR-independent Treg expansion in vitro, which was critically dependent on noncanonical NF-\u03baB signaling. OX40L-JAG1\u2013expanded Tregs showed sustained lineage stability as indicated by stable demethylation marks in Treg signature genes such as Foxp3, Il2ra, Ctla4, Ikzf2, and Ikzf4. Furthermore, OX40L-JAG1 treatment significantly increased CTLA4+ and TIGIT+ Tregs and alleviated experimental autoimmune thyroiditis in mice. Relevance of our findings to humans became apparent when human OX40L and JAG1 induced TCR-independent selective expansion of human Tregs in thymocyte cultures and increased human Tregs in the liver tissue of humanized NSG mice. Our findings suggest that OX40L-JAG1\u2013induced TCR-independent Treg proliferation is a conserved mechanism that can be used to expand lineage-stable Tregs to treat autoimmune diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.1900530","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T20:25:15Z","timestamp":1573244715000},"page":"3225-3236","source":"Crossref","is-referenced-by-count":11,"title":["OX40L-JAG1\u2013Induced Expansion of Lineage-Stable Regulatory T Cells Involves Noncanonical NF-\u03baB Signaling"],"prefix":"10.1093","volume":"203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-6938","authenticated-orcid":false,"given":"Prabhakaran","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois College of Medicine , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swarali Surendra","family":"Lele","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois College of Medicine , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandhana K","family":"Ragothaman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois College of Medicine , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Raghunathan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois College of Medicine , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan L","family":"Epstein","sequence":"additional","affiliation":[{"name":"Department of Pathology, Keck School of Medicine at University of Southern California , Los Angeles, CA 900933"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7803-7338","authenticated-orcid":false,"given":"Shigeru","family":"Chiba","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba , Tsukuba 305-8575 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9815-9850","authenticated-orcid":false,"given":"Bellur S","family":"Prabhakar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois College of Medicine , Chicago, IL 60612"},{"name":"Department of Ophthalmology, University of Illinois College of Medicine , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,12,15]]},"reference":[{"key":"2025030417544715200_r1","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"2025030417544715200_r2","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev.immunol.25.022106.141623","article-title":"Regulatory T cells: mechanisms of differentiation and function","volume":"30","author":"Josefowicz","year":"2012","journal-title":"Annu. 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