{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:29:09Z","timestamp":1791030549551,"version":"4.1.0"},"reference-count":49,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,4,1]]},"abstract":"<jats:p>There have been several reports that TNF-related apoptosis-inducing ligand (TRAIL) has the ability to suppress the development of experimental autoimmune diseases, including a mouse model of experimental autoimmune encephalomyelitis, a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus, in mice and experimental autoimmune thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examined TRAIL effects on CD4+CD25+ regulatory T cells. CD4+CD25+ T cells prepared from mouse thyroglobulin (mTg)-immunized CBA\/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4+CD25+ T cells included both CD4+CD25+CD45RBLow (regulatory) and CD4+CD25+CD45RBHigh (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4+CD25+CD45RBLow T cells compared with mice immunized with mTg alone. CD4+CD25+CD45RBLow T cells expressed much higher levels of the forkhead family transcription factor, IL-10, and TGF\u03b21 than CD4+CD25+CD45RBHigh T cells, and these cells can completely suppress the proliferation of the mTg-primed splenocytes in lower concentrations than the unfractionated CD4+CD25+ T cells. Furthermore, transfer of these cells into CBA\/J mice prior to mTg-primed splenocyte injection could markedly reduce the frequency and severity of EAT development. CD4+CD25+CD45RBLow T cells were more effective at suppressing histological thyroiditis than unfractionated cells. These results indicated that TRAIL can increase the number of mTg-specific CD4+CD25+CD45RBLow T cells, inhibiting autoimmune responses and preventing the progression of EAT. These findings reveal a novel mechanism by which TRAIL could inhibit autoimmune disease.<\/jats:p>","DOI":"10.1210\/en.2008-1389","type":"journal-article","created":{"date-parts":[[2008,11,14]],"date-time":"2008-11-14T01:54:09Z","timestamp":1226627649000},"page":"2000-2007","source":"Crossref","is-referenced-by-count":41,"title":["Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Inhibits Experimental Autoimmune Thyroiditis by the Expansion of CD4+CD25+ Regulatory T Cells"],"prefix":"10.1210","volume":"150","author":[{"given":"Su He","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwo-Hsiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyi","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Van Antwerp","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"James R.","family":"Baker","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2008,11,13]]},"reference":[{"key":"2020071612254149200_R1","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.4049\/jimmunol.168.5.2470","article-title":"A unique combination of inflammatory cytokines enhances apoptosis of thyroid follicular cells and transforms nondestructive to destructive thyroiditis in experimental autoimmune thyroiditis.","volume":"168","author":"Wang","year":"2002","journal-title":"J Immunol"},{"key":"2020071612254149200_R2","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1210\/me.2004-0286","article-title":"Induction and regulation of Fas-mediated apoptosis in human thyroid epithelial cells.","volume":"19","author":"Mezosi","year":"2005","journal-title":"Mol Endocrinol"},{"key":"2020071612254149200_R3","doi-asserted-by":"crossref","first-page":"4844","DOI":"10.1210\/en.2007-0126","article-title":"Microarray analysis of cytokine activation of apoptosis pathways in the thyroid.","volume":"148","author":"Wang","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612254149200_R4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.0105-2896.2006.00417.x","article-title":"Human regulatory T cells and their role in autoimmune disease.","volume":"212","author":"Baecher-Allan","year":"2006","journal-title":"Immunol Rev"},{"key":"2020071612254149200_R5","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.4049\/jimmunol.178.4.2458","article-title":"FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells.","volume":"178","author":"Daniel","year":"2007","journal-title":"J Immunol"},{"key":"2020071612254149200_R6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ijpara.2007.07.006","article-title":"Natural regulatory CD4(+)CD25(+)FOXP3(+) T cells control the production of pro-inflammatory cytokines during plasmodium chabaudi adami infection and do not contribute to immune evasion.","volume":"38","author":"Cambos","year":"2008","journal-title":"Int J Parasitol"},{"key":"2020071612254149200_R7","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nri2061","article-title":"FOXP3 modifies the phenotypic and functional properties of regulatory T cells.","volume":"7","author":"Campbell","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"2020071612254149200_R8","doi-asserted-by":"crossref","first-page":"5138","DOI":"10.1073\/pnas.0501675102","article-title":"Foxp3 interacts with nuclear factor of activated T cells and NF-\u03baB to repress cytokine gene expression and effector functions of T helper cells.","volume":"102","author":"Bettelli","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612254149200_R9","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/nri2138","article-title":"Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans.","volume":"7","author":"Roncarolo","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"2020071612254149200_R10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00281-006-0021-8","article-title":"Regulatory T cells in experimental autoimmune disease.","volume":"28","author":"Suri-Payer","year":"2006","journal-title":"Semin Immunopathol Springer"},{"key":"2020071612254149200_R11","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/j.1440-1711.2005.01358.x","article-title":"TNF-related apoptosis-inducing ligand (TRAIL)\/Apo2L suppresses experimental autoimmune encephalomyelitis in mice.","volume":"83","author":"Cretney","year":"2005","journal-title":"Immunol Cell Biol"},{"key":"2020071612254149200_R12","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/sj.gt.3301881","article-title":"Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium.","volume":"10","author":"Yao","year":"2003","journal-title":"Gene Ther"},{"key":"2020071612254149200_R13","doi-asserted-by":"crossref","first-page":"918","DOI":"10.4049\/jimmunol.178.2.918","article-title":"Involvement of regulatory T cells in the experimental autoimmune encephalomyelitis-preventive effect of dendritic cells expressing myelin oligodendrocyte glycoprotein plus TRAIL.","volume":"178","author":"Hirata","year":"2007","journal-title":"J Immunol"},{"key":"2020071612254149200_R14","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1038\/sj.cdd.4402220","article-title":"Involvement of cellular death in TRAIL\/DR5-dependent suppression induced by CD4(+)CD25(+) regulatory T cells.","volume":"14","author":"Ren","year":"2007","journal-title":"Cell Death Differ"},{"key":"2020071612254149200_R15","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.2337\/diabetes.52.8.1967","article-title":"Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice.","volume":"52","author":"Mi","year":"2003","journal-title":"Diabetes"},{"key":"2020071612254149200_R16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1158\/0008-5472.CAN-05-3445","article-title":"Proinflammatory CD4+CD45RB(hi) lymphocytes promote mammary and intestinal carcinogenesis in Apc(Min\/+) mice.","volume":"66","author":"Rao","year":"2006","journal-title":"Cancer Res"},{"key":"2020071612254149200_R17","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1097\/01.TP.0000072373.77323.D4","article-title":"Alteration in CD45RBhi\/CD45RBlo T-cell ratio following CD45RB monoclonal-antibody therapy occurs by selective deletion of CD45RBhi effector cells.","volume":"76","author":"Luke","year":"2003","journal-title":"Transplantation"},{"key":"2020071612254149200_R18","doi-asserted-by":"crossref","first-page":"787","DOI":"10.4049\/jimmunol.172.2.787","article-title":"CD7 and CD28 are required for murine CD4+CD25+ regulatory T cell homeostasis and prevention of thyroiditis.","volume":"172","author":"Sempowski","year":"2004","journal-title":"J Immunol"},{"key":"2020071612254149200_R19","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.jaut.2007.07.008","article-title":"CD4(+)CD25(+) naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2(h4) mice.","volume":"29","author":"Nagayama","year":"2007","journal-title":"J Autoimmun"},{"key":"2020071612254149200_R20","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.2741\/1876","article-title":"Tolerance to autoimmune thyroiditis: (CD4+)CD25+ regulatory T cells influence susceptibility but do not supersede MHC class II restriction.","volume":"11","author":"Morris","year":"2006","journal-title":"Front Biosci"},{"key":"2020071612254149200_R21","doi-asserted-by":"crossref","first-page":"5724","DOI":"10.1210\/en.2007-1024","article-title":"The link between Graves\u2019 disease and Hashimoto\u2019s thyroiditis: a role for regulatory T cells.","volume":"148","author":"McLachlan","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612254149200_R22","doi-asserted-by":"crossref","first-page":"8471","DOI":"10.1158\/0008-5472.CAN-05-0934","article-title":"Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4+ CD25+ regulatory T cell-depleted mice.","volume":"65","author":"Wei","year":"2005","journal-title":"Cancer Res"},{"key":"2020071612254149200_R23","doi-asserted-by":"crossref","first-page":"7433","DOI":"10.4049\/jimmunol.174.11.7433","article-title":"Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+CD25+ T cells.","volume":"174","author":"Verginis","year":"2005","journal-title":"J Immunol"},{"key":"2020071612254149200_R24","doi-asserted-by":"crossref","first-page":"7006","DOI":"10.4049\/jimmunol.174.11.7006","article-title":"IL-10-producing CD4+CD25+ regulatory T cells play a critical role in granulocyte-macrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis.","volume":"174","author":"Gangi","year":"2005","journal-title":"J Immunol"},{"key":"2020071612254149200_R25","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/j.1365-2249.2006.03303.x","article-title":"Depletion of CD4+CD25+ regulatory T cells exacerbates sodium iodide-induced experimental autoimmune thyroiditis in human leucocyte antigen DR3 (DRB1*0301) transgenic class II-knockout non-obese diabetic mice.","volume":"147","author":"Flynn","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"2020071612254149200_R26","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1530\/eje.0.1480383","article-title":"Type-1 response in peripheral CD4+ and CD8+ T cells from patients with Hashimoto\u2019s thyroiditis.","volume":"148","author":"Mazziotti","year":"2003","journal-title":"Eur J Endocrinol"},{"key":"2020071612254149200_R27","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1210\/jc.2003-030697","article-title":"Interleukin-1\u03b2 and tumor necrosis factor (TNF)-\u03b1 sensitize human thyroid epithelial cells to TNF-related apoptosis-inducing ligand-induced apoptosis through increases in procaspase-7 and bid, and the down-regulation of p44\/42 mitogen-activated protein kinase activity.","volume":"89","author":"Mezosi","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612254149200_R28","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1210\/en.2005-0627","article-title":"Death ligand tumor necrosis factor-related apoptosis-inducing ligand inhibits experimental autoimmune thyroiditis.","volume":"146","author":"Wang","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612254149200_R29","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.4049\/jimmunol.166.6.3789","article-title":"IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo.","volume":"166","author":"Hara","year":"2001","journal-title":"J Immunol"},{"key":"2020071612254149200_R30","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.4049\/jimmunol.179.6.3578","article-title":"Rapid suppression of cytokine transcription in human CD4+CD25 T cells by CD4+Foxp3+ regulatory T cells: independence of IL-2 consumption, TGF-\u03b2, and various inhibitors of TCR signaling.","volume":"179","author":"Oberle","year":"2007","journal-title":"J Immunol"},{"key":"2020071612254149200_R31","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/j.0300-9475.2004.01410.x","article-title":"Circulating CD4+CD25+ and CD4+CD25+ T cells in myasthenia gravis and in relation to thymectomy.","volume":"59","author":"Huang","year":"2004","journal-title":"Scand J Immunol"},{"key":"2020071612254149200_R32","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1210\/jc.2005-2337","article-title":"Regulatory T cells in human autoimmune thyroid disease.","volume":"91","author":"Marazuela","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612254149200_R33","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jaut.2007.02.016","article-title":"The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts.","volume":"28","author":"Ban","year":"2007","journal-title":"J Autoimmun"},{"key":"2020071612254149200_R34","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/intimm\/dxg061","article-title":"Targeted engagement of CTLA-4 prevents autoimmune thyroiditis.","volume":"15","author":"Vasu","year":"2003","journal-title":"Int Immunol"},{"key":"2020071612254149200_R35","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.4049\/jimmunol.170.11.5511","article-title":"Selective induction of dendritic cells using granulocyte macrophage-colony stimulating factor, but not fms-like tyrosine kinase receptor 3-ligand, activates thyroglobulin-specific CD4+\/CD25+ T cells and suppresses experimental autoimmune thyroiditis.","volume":"170","author":"Vasu","year":"2003","journal-title":"J Immunol"},{"key":"2020071612254149200_R36","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1084\/jem.177.3.627","article-title":"Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential.","volume":"177","author":"Fowell","year":"1993","journal-title":"J Exp Med"},{"key":"2020071612254149200_R37","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/1074-7613(94)90045-0","article-title":"Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.","volume":"1","author":"Powrie","year":"1994","journal-title":"Immunity"},{"key":"2020071612254149200_R38","doi-asserted-by":"crossref","first-page":"5353","DOI":"10.4049\/jimmunol.163.10.5353","article-title":"CD4+ CD45RB low-density cells from untreated mice prevent acute allograft rejection.","volume":"163","author":"Davies","year":"1999","journal-title":"J Immunol"},{"key":"2020071612254149200_R39","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat Immunol"},{"key":"2020071612254149200_R40","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1126\/science.1079490","article-title":"Control of regulatory T cell development by the transcription factor Foxp3.","volume":"299","author":"Hori","year":"2003","journal-title":"Science"},{"key":"2020071612254149200_R41","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1084\/jem.20062076","article-title":"CCR4-dependent regulatory T cell function in inflammatory bowel disease.","volume":"204","author":"Yuan","year":"2007","journal-title":"J Exp Med"},{"key":"2020071612254149200_R42","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1080\/17402520400004201","article-title":"Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis?","volume":"11","author":"Wen","year":"2004","journal-title":"Clin Dev Immunol"},{"key":"2020071612254149200_R43","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/intimm\/dxh367","article-title":"Targeting CD45RB alters T cell migration and delays viral clearance.","volume":"18","author":"Lim","year":"2006","journal-title":"Int Immunol"},{"key":"2020071612254149200_R44","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/art.22394","article-title":"Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells.","volume":"56","author":"Gonzalez-Rey","year":"2007","journal-title":"Arthritis Rheum"},{"key":"2020071612254149200_R45","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1136\/ard.2006.068320","article-title":"Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis.","volume":"66","author":"Behrens","year":"2007","journal-title":"Ann Rheum Dis"},{"key":"2020071612254149200_R46","first-page":"514","article-title":"Increased CD4+ CD25+ T regulatory cell activity in trauma patients depresses protective Th1 immunity.","volume":"244","author":"MacConmara","year":"2006","journal-title":"Ann Surg"},{"key":"2020071612254149200_R47","doi-asserted-by":"crossref","first-page":"755","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":"2020071612254149200_R48","doi-asserted-by":"crossref","first-page":"7259","DOI":"10.4049\/jimmunol.173.12.7259","article-title":"CD25-T cells generate CD25+ Foxp3+ regulatory T cells by peripheral expansion.","volume":"173","author":"Curotto de Lafaille","year":"2004","journal-title":"J Immunol"},{"key":"2020071612254149200_R49","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/ni1265","article-title":"Inducing and expanding regulatory T cell populations by foreign antigen.","volume":"6","author":"Kretschmer","year":"2005","journal-title":"Nat Immunol"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/4\/2000\/9008472\/endo2000.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/4\/2000\/9008472\/endo2000.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,21]],"date-time":"2023-05-21T02:09:04Z","timestamp":1684634944000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/150\/4\/2000\/2455906"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11,13]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,4,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2008-1389","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,11,13]]}}}