{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T21:45:31Z","timestamp":1771883131487,"version":"3.50.1"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"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":[[2014,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg\/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7\u2013driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R\u2212\/\u2212 cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1302966","type":"journal-article","created":{"date-parts":[[2014,10,23]],"date-time":"2014-10-23T01:51:33Z","timestamp":1414029093000},"page":"4845-4858","source":"Crossref","is-referenced-by-count":21,"title":["Inflammation and Lymphopenia Trigger Autoimmunity by Suppression of IL-2\u2013Controlled Regulatory T Cell and Increase of IL-21\u2013Mediated Effector T Cell Expansion"],"prefix":"10.1093","volume":"193","author":[{"given":"Nina","family":"Chevalier","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University Medical Centre Freiburg , 79106 Freiburg ,","place":["Germany"]},{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]},{"name":"Immunology Department, Garvan Institute of Medical Research, Sydney , New South Wales 2010 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison N","family":"Thorburn","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurence","family":"Macia","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Tan","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Juglair","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideo","family":"Yagita","sequence":"additional","affiliation":[{"name":"Department of Immunology, Juntendo University School of Medicine , 113-8421 Tokyo ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip M","family":"Hansbro","sequence":"additional","affiliation":[{"name":"Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle , Newcastle, New South Wales 2300 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R","family":"Mackay","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, Monash University Clayton, Melbourne , Victoria 3088 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,11,15]]},"reference":[{"key":"2025030707443132600_r1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1165\/rcmb.2009-0342TR","article-title":"Harnessing regulatory T cells to suppress asthma: from potential to therapy","volume":"43","author":"Thorburn","year":"2010","journal-title":"Am. 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