{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:19:07Z","timestamp":1790173147555,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"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":[[2015,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is highly tyrosine phosphorylated upon engagement of the TCR. Phosphorylated LAT binds Grb2, Gads, and phospholipase C (PLC)\u03b31 to mediate T cell activation, proliferation, and cytokine production. T cells from mice harboring a mutation at the PLC\u03b31 binding site of LAT (Y136F) have impaired calcium flux and Erk activation. Interestingly, these T cells are highly activated, resulting in the development of a lymphoproliferative syndrome in these mice. CD4+ T cells in LATY136F mice are Th2 skewed, producing large amounts of IL-4. In this study, we showed that the LATY136F T cells could also overproduce IL-6 due to activated NF-\u03baB, AKT, and p38 pathways. By crossing LATY136F mice with IL-6\u2013deficient mice, we demonstrated that IL-6 is required for uncontrolled T cell expansion during the early stage of disease development. Reduced CD4+ T cell expansion was not due to a further block in thymocyte development or an increase in the number of regulatory T cells, but was caused by reduction in cell survival. In aged IL-6\u2212\/\u2212 LATY136F mice, CD4+ T cells began to hyperproliferate and induced splenomegaly; however, isotype switching and autoantibody production were diminished. Our data indicated that the LAT\u2013PLC\u03b31 interaction is important for controlling IL-6 production by T cells and demonstrated a critical role of IL-6 in the development of this lymphoproliferative syndrome.<\/jats:p>","DOI":"10.4049\/jimmunol.1403187","type":"journal-article","created":{"date-parts":[[2015,6,2]],"date-time":"2015-06-02T13:51:56Z","timestamp":1433253116000},"page":"695-705","source":"Crossref","is-referenced-by-count":19,"title":["The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity"],"prefix":"10.1093","volume":"195","author":[{"given":"Sarah A","family":"O\u2019Brien","sequence":"first","affiliation":[{"name":"Department of Immunology, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University Medical Center , Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,7,15]]},"reference":[{"key":"2025030703431659200_r1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.2147\/TCRM.S3470","article-title":"Interleukin-6 inhibitors in the treatment of rheumatoid arthritis","volume":"4","author":"Hennigan","year":"2008","journal-title":"Ther Clin Risk Manag"},{"key":"2025030703431659200_r2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1359-6101(98)80005-1","article-title":"Signaling mechanisms through gp130: a model of the cytokine system","volume":"8","author":"Hirano","year":"1997","journal-title":"Cytokine Growth Factor Rev."},{"key":"2025030703431659200_r3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.molmed.2007.12.007","article-title":"The wolf in sheep\u2019s clothing: the role of interleukin-6 in immunity, inflammation and cancer","volume":"14","author":"Naugler","year":"2008","journal-title":"Trends Mol. Med."},{"key":"2025030703431659200_r4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20030407","article-title":"Principles of interleukin (IL)-6-type cytokine signalling and its regulation","volume":"374","author":"Heinrich","year":"2003","journal-title":"Biochem. J."},{"key":"2025030703431659200_r5","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/ijc.23261","article-title":"Interleukin-6 activates PI3K\/Akt pathway and regulates cyclin A1 to promote prostate cancer cell survival","volume":"122","author":"Wegiel","year":"2008","journal-title":"Int. J. Cancer"},{"key":"2025030703431659200_r6","doi-asserted-by":"crossref","first-page":"4652","DOI":"10.4049\/jimmunol.161.9.4652","article-title":"Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice","volume":"161","author":"Takeda","year":"1998","journal-title":"J. Immunol."},{"key":"2025030703431659200_r7","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1084\/jem.191.6.915","article-title":"Activation-induced inhibition of interleukin 6-mediated T cell survival and signal transducer and activator of transcription 1 signaling","volume":"191","author":"Teague","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r8","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1002\/eji.201040391","article-title":"IL-6: regulator of Treg\/Th17 balance","volume":"40","author":"Kimura","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025030703431659200_r9","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature04753","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells","volume":"441","author":"Bettelli","year":"2006","journal-title":"Nature"},{"key":"2025030703431659200_r10","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature04754","article-title":"Transforming growth factor-\u03b2 induces development of the TH17 lineage","volume":"441","author":"Mangan","year":"2006","journal-title":"Nature"},{"key":"2025030703431659200_r11","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.4049\/jimmunol.174.5.2720","article-title":"IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation","volume":"174","author":"Yang","year":"2005","journal-title":"J. Immunol."},{"key":"2025030703431659200_r12","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/icb.2012.17","article-title":"IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells","volume":"90","author":"Diehl","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"2025030703431659200_r13","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1084\/jem.20092253","article-title":"Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis","volume":"207","author":"Feng","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r14","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1084\/jem.20071133","article-title":"IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+ T cells","volume":"205","author":"Tajima","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r15","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1084\/jem.20052187","article-title":"Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3\/IL-7-dependent homeostatic proliferation of CD4+ T cells","volume":"203","author":"Sawa","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r16","doi-asserted-by":"crossref","first-page":"23355","DOI":"10.1074\/jbc.M000404200","article-title":"Association of Grb2, Gads, and phospholipase C-\u03b31 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling","volume":"275","author":"Zhang","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2025030703431659200_r17","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1093\/intimm\/11.6.943","article-title":"Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line","volume":"11","author":"Zhang","year":"1999","journal-title":"Int. Immunol."},{"key":"2025030703431659200_r18","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1126\/science.1069066","article-title":"A LAT mutation that inhibits T cell development yet induces lymphoproliferation","volume":"296","author":"Sommers","year":"2002","journal-title":"Science"},{"key":"2025030703431659200_r19","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1126\/science.1069057","article-title":"Induction of T helper type 2 immunity by a point mutation in the LAT adaptor","volume":"296","author":"Aguado","year":"2002","journal-title":"Science"},{"key":"2025030703431659200_r20","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1074-7613(00)80032-1","article-title":"Essential role of LAT in T cell development","volume":"10","author":"Zhang","year":"1999","journal-title":"Immunity"},{"key":"2025030703431659200_r21","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.4049\/jimmunol.1302493","article-title":"The role of LAT-PLC\u03b31 interaction in \u03b3\u03b4 T cell development and homeostasis","volume":"192","author":"Sullivan","year":"2014","journal-title":"J. Immunol."},{"key":"2025030703431659200_r22","first-page":"4443","article-title":"Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide","volume":"14","author":"Dendorfer","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"2025030703431659200_r23","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/jcp.22047","article-title":"FAK activation is required for TNF-\u03b1-induced IL-6 production in myoblasts","volume":"223","author":"Tseng","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"2025030703431659200_r24","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/1476-4598-10-150","article-title":"IL-17 induces AKT-dependent IL-6\/JAK2\/STAT3 activation and tumor progression in hepatocellular carcinoma","volume":"10","author":"Gu","year":"2011","journal-title":"Mol. Cancer"},{"key":"2025030703431659200_r25","doi-asserted-by":"crossref","first-page":"R120","DOI":"10.1186\/ar1038","article-title":"IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-\u03baB- and PI3-kinase\/Akt-dependent pathways","volume":"6","author":"Hwang","year":"2004","journal-title":"Arthritis Res. Ther."},{"key":"2025030703431659200_r26","first-page":"2327","article-title":"Activation of interleukin-6 gene expression through the NF-\u03baB transcription factor","volume":"10","author":"Libermann","year":"1990","journal-title":"Mol. Cell. Biol."},{"key":"2025030703431659200_r27","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.immuni.2006.01.001","article-title":"TGF\u03b2 in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells","volume":"24","author":"Veldhoen","year":"2006","journal-title":"Immunity"},{"key":"2025030703431659200_r28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1084\/jem.20050903","article-title":"LAT-mediated signaling in CD4+CD25+ regulatory T cell development","volume":"203","author":"Koonpaew","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r29","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.4049\/jimmunol.0902876","article-title":"The role of the LAT-PLC-\u03b31 interaction in T regulatory cell function","volume":"184","author":"Chuck","year":"2010","journal-title":"J. Immunol."},{"key":"2025030703431659200_r30","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1084\/jem.20021633","article-title":"Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide","volume":"197","author":"Caramalho","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r31","doi-asserted-by":"crossref","first-page":"R433","DOI":"10.1186\/ar1212","article-title":"Direct Toll-like receptor 2 mediated co-stimulation of T cells in the mouse system as a basis for chronic inflammatory joint disease","volume":"6","author":"Sobek","year":"2004","journal-title":"Arthritis Res. Ther."},{"key":"2025030703431659200_r32","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1165\/rcmb.2008-0302OC","article-title":"IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusins","volume":"41","author":"Waxman","year":"2009","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030703431659200_r33","doi-asserted-by":"crossref","first-page":"4761","DOI":"10.4049\/jimmunol.174.8.4761","article-title":"IL-6 increases primed cell expansion and survival","volume":"174","author":"Rochman","year":"2005","journal-title":"J. Immunol."},{"key":"2025030703431659200_r34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1084\/jem.20081571","article-title":"The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells","volume":"206","author":"Dienz","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025030703431659200_r35","doi-asserted-by":"crossref","first-page":"23814","DOI":"10.1074\/jbc.M909695199","article-title":"p38 MAPK and NF-\u03baB collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system","volume":"275","author":"Craig","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2025030703431659200_r36","doi-asserted-by":"crossref","first-page":"784","DOI":"10.4049\/jimmunol.1001562","article-title":"\u03b2-Catenin inhibits T cell activation by selective interference with linker for activation of T cells-phospholipase C-\u03b31 phosphorylation","volume":"186","author":"Driessens","year":"2011","journal-title":"J. Immunol."},{"key":"2025030703431659200_r37","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.4049\/jimmunol.180.3.1565","article-title":"Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells","volume":"180","author":"Wang","year":"2008","journal-title":"J. Immunol."},{"key":"2025030703431659200_r38","doi-asserted-by":"crossref","first-page":"9589","DOI":"10.1073\/pnas.0501794102","article-title":"IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation","volume":"102","author":"McLoughlin","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030703431659200_r39","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1002\/eji.200425237","article-title":"Interleukin-6 is a direct mediator of T cell migration","volume":"34","author":"Weissenbach","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"2025030703431659200_r40","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1136\/bmj.327.7419.856","article-title":"A wolf in sheep\u2019s clothing: a critical look at the ethics of drug taking","volume":"327","author":"Heath","year":"2003","journal-title":"BMJ"},{"key":"2025030703431659200_r41","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1182\/blood.V74.4.1360.1360","article-title":"Pathogenic significance of interleukin-6 (IL-6\/BSF-2) in Castleman\u2019s disease","volume":"74","author":"Yoshizaki","year":"1989","journal-title":"Blood"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/2\/695\/61502076\/1403187.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/2\/695\/61502076\/1403187.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T03:44:03Z","timestamp":1741319043000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/2\/695\/7961112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7]]},"references-count":41,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1403187","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,7]]},"published":{"date-parts":[[2015,7]]}}}