{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:19:57Z","timestamp":1789787997455,"version":"4.0.1"},"reference-count":84,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell\/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part <jats:italic>via<\/jats:italic> promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell\/GC responses and autoimmunity <jats:italic>via<\/jats:italic> neighboring GC-Tfh cells.<\/jats:p>","DOI":"10.3389\/fimmu.2021.620437","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T05:44:15Z","timestamp":1618379055000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1"],"prefix":"10.3389","volume":"12","author":[{"given":"Shimeng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danli","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srija","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Sleasman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ping","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.04.011","article-title":"T Follicular Helper Cell Biology: A Decade of Discovery and Diseases","volume":"50","author":"Crotty","year":"2019","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055605","article-title":"Follicular Helper T Cells","volume":"34","author":"Vinuesa","year":"2016","journal-title":"Annu Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.immuni.2018.10.012","article-title":"The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus","volume":"49","author":"Kim","year":"2018","journal-title":"Immunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170580","article-title":"B cell-derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity","volume":"214","author":"Arkatkar","year":"2017","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1177\/0961203314567750","article-title":"Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production","volume":"24","author":"Zhang","year":"2015","journal-title":"Lupus"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502283","article-title":"The Lupus Susceptibility Gene Pbx1 Regulates the Balance between Follicular Helper T Cell and Regulatory T Cell Differentiation","volume":"197","author":"Choi","year":"2016","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"491","DOI":"10.4049\/jimmunol.1502241","article-title":"Loss of Immune Tolerance Is Controlled by ICOS in Sle1 Mice","volume":"197","author":"Mittereder","year":"2016","journal-title":"J Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.05.012","article-title":"OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response","volume":"42","author":"Jacquemin","year":"2015","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1172\/JCI76238","article-title":"Follicular helper T cell signature in type 1 diabetes","volume":"125","author":"Kenefeck","year":"2015","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175870","article-title":"Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation","volume":"325","author":"Johnston","year":"2009","journal-title":"Science"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of T follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911573106","article-title":"Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase","volume":"106","author":"Gigoux","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.07.002","article-title":"The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment","volume":"31","author":"Yu","year":"2009","journal-title":"Immunity"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.07.015","article-title":"Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling","volume":"33","author":"Deenick","year":"2010","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.immuni.2012.11.020","article-title":"Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype","volume":"38","author":"Baumjohann","year":"2013","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1704","article-title":"The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding","volume":"10","author":"Fazilleau","year":"2009","journal-title":"Nat Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.03.023","article-title":"ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6","volume":"34","author":"Choi","year":"2011","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1105774108","article-title":"Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development","volume":"108","author":"Hu","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.4.2340","article-title":"The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo","volume":"175","author":"Akiba","year":"2005","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.8.1115","article-title":"Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers","volume":"190","author":"Walker","year":"1999","journal-title":"J Exp Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1690","article-title":"The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells","volume":"10","author":"Bauquet","year":"2009","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-11-4494","article-title":"Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help","volume":"106","author":"Hardtke","year":"2005","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12739","article-title":"T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr-cell compartments","volume":"288","author":"Fonseca","year":"2019","journal-title":"Immunol Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12411","article-title":"T follicular regulatory cells","volume":"271","author":"Sage","year":"2016","journal-title":"Immunol Rev"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170901","article-title":"Deficiency in T follicular regulatory cells promotes autoimmunity","volume":"215","author":"Fu","year":"2018","journal-title":"J Exp Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-08-300731","article-title":"Negative regulation of mTOR activation by diacylglycerol kinases","volume":"117","author":"Gorentla","year":"2011","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","first-page":"ra55","DOI":"10.1126\/scisignal.2005169","article-title":"T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10","volume":"7","author":"Hamilton","year":"2014","journal-title":"Sci Signal"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2013.05.002","article-title":"mTOR and lymphocyte metabolism","volume":"25","author":"Zeng","year":"2013","journal-title":"Curr Opin Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.immuni.2017.08.011","article-title":"The Kinase mTORC1 Promotes the Generation and Suppressive Function of Follicular Regulatory T Cells","volume":"47","author":"Xu","year":"2017","journal-title":"Immunity"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.17936","article-title":"Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses","volume":"5","author":"Yang","year":"2016","journal-title":"eLife"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.08.017","article-title":"mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation","volume":"45","author":"Zeng","year":"2016","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.immuni.2015.08.017","article-title":"The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells","volume":"43","author":"Ray","year":"2015","journal-title":"Immunity"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.08698","article-title":"Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation","volume":"4","author":"Ramiscal","year":"2015","journal-title":"eLife"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602282103","article-title":"TSC1\/TSC2 and Rheb have different effects on TORC1 and TORC2 activity","volume":"103","author":"Yang","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1042\/BST0370217","article-title":"A complex interplay between Akt, TSC2 and the two mTOR complexes","volume":"37","author":"Huang","year":"2009","journal-title":"Biochem Soc Trans"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.06.009","article-title":"TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1","volume":"47","author":"Dibble","year":"2012","journal-title":"Mol Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.035","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"169","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2015.07.022","article-title":"mTOR and its tight regulation for iNKT cell development and effector function","volume":"68","author":"Yang","year":"2015","journal-title":"Mol Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141411","article-title":"Regulation of T-cell survival and mitochondrial homeostasis by TSC1","volume":"41","author":"O\u2019Brien","year":"2011","journal-title":"Eur J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2068","article-title":"The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function","volume":"12","author":"Yang","year":"2011","journal-title":"Nat Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003968","article-title":"The tuberous sclerosis complex-mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells","volume":"187","author":"Wu","year":"2011","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e30592","DOI":"10.1371\/journal.pone.0030592","article-title":"TSC1\/2 signaling complex is essential for peripheral naive CD8+ T cell survival and homeostasis in mice","volume":"7","author":"Zhang","year":"2012","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01816-14","article-title":"Role of tumor suppressor TSC1 in regulating antigen-specific primary and memory CD8 T cell responses to bacterial infection","volume":"82","author":"Krishna","year":"2014","journal-title":"Infect Immun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1404264111","article-title":"Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs","volume":"111","author":"Shrestha","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119744109","article-title":"Tumor suppressor TSC1 is critical for T-cell anergy","volume":"109","author":"Xie","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-353342","article-title":"Regulation of mast cell survival and function by tuberous sclerosis complex 1","volume":"119","author":"Shin","year":"2012","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s12858-016-0069-6","article-title":"Sustained activation of mTORC1 in macrophages increases AMPKalpha-dependent autophagy to maintain cellular homeostasis","volume":"17","author":"Pan","year":"2016","journal-title":"BMC Biochem"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e2553","DOI":"10.1038\/cddis.2016.487","article-title":"Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response","volume":"8","author":"Luo","year":"2017","journal-title":"Cell Death Dis"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201041336","article-title":"Direct activation of mTOR in B lymphocytes confers impairment in B-cell maturation andloss of marginal zone B cells","volume":"41","author":"Benhamron","year":"2011","journal-title":"Eur J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-235408","article-title":"Disruption of TSC1\/2 signaling complex reveals a checkpoint governing thymic CD4+ CD25+ Foxp3+ regulatory T-cell development in mice","volume":"27","author":"Chen","year":"2013","journal-title":"FASEB J"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69751","article-title":"TSC1 regulates the balance between effector and regulatory T cells","volume":"123","author":"Park","year":"2013","journal-title":"J Clin Invest"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/j.immuni.2017.06.005","article-title":"Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase","volume":"46","author":"Ersching","year":"2017","journal-title":"Immunity"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.5.525","article-title":"A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells","volume":"11","author":"Kwiatkowski","year":"2002","journal-title":"Hum Mol Genet"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00227-8","article-title":"A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival","volume":"15","author":"Lee","year":"2001","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","first-page":"e0127527","DOI":"10.1371\/journal.pone.0127527","article-title":"TSC1 Promotes B Cell Maturation but Is Dispensable for Germinal Center Formation","volume":"10","author":"Ci","year":"2015","journal-title":"PloS One"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.12.004","article-title":"Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation","volume":"38","author":"Vogel","year":"2013","journal-title":"Immunity"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141432","article-title":"ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2","volume":"212","author":"Weber","year":"2015","journal-title":"J Exp Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00480","article-title":"The Transcription Factor c-Maf Promotes the Differentiation of Follicular Helper T Cells","volume":"8","author":"Andris","year":"2017","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103246","article-title":"Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation","volume":"188","author":"Kroenke","year":"2012","journal-title":"J Immunol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"190","DOI":"10.4049\/jimmunol.0903505","article-title":"Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150)","volume":"185","author":"Yusuf","year":"2010","journal-title":"J Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171129","article-title":"ICAMs support B cell interactions with T follicular helper cells and promote clonal selection","volume":"214","author":"Zaretsky","year":"2017","journal-title":"J Exp Med"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.09.018","article-title":"The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance","volume":"45","author":"Meli","year":"2016","journal-title":"Immunity"},{"key":"B63","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.immuni.2018.03.027","article-title":"T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate","volume":"48","author":"Ise","year":"2018","journal-title":"Immunity"},{"key":"B64","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1038\/s41467-018-04392-5","article-title":"mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis","volume":"9","author":"Chapman","year":"2018","journal-title":"Nat Commun"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nature12297","article-title":"mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function","volume":"499","author":"Zeng","year":"2013","journal-title":"Nature"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800529","article-title":"Active mTORC2 Signaling in Naive T Cells Suppresses Bone Marrow Homing by Inhibiting CXCR4 Expression","volume":"201","author":"Arojo","year":"2018","journal-title":"J Immunol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1603","article-title":"Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking","volume":"9","author":"Sinclair","year":"2008","journal-title":"Nat Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01127","article-title":"The Kinase Complex mTOR Complex 2 Promotes the Follicular Migration and Functional Maturation of Differentiated Follicular Helper CD4(+) T Cells During Viral Infection","volume":"9","author":"Hao","year":"2018","journal-title":"Front Immunol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/s41467-017-00348-3","article-title":"The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity","volume":"8","author":"Yi","year":"2017","journal-title":"Nat Commun"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001730","article-title":"Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction","volume":"185","author":"Rolf","year":"2010","journal-title":"J Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2642","article-title":"The microRNA cluster miR-17 approximately 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression","volume":"14","author":"Baumjohann","year":"2013","journal-title":"Nat Immunol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2648","article-title":"MicroRNAs of the miR-17 approximately 92 family are critical regulators of T(FH) differentiation","volume":"14","author":"Kang","year":"2013","journal-title":"Nat Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/nature13803","article-title":"T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction","volume":"517","author":"Liu","year":"2015","journal-title":"Nature"},{"key":"B74","doi-asserted-by":"publisher","first-page":"6436","DOI":"10.1038\/ncomms7436","article-title":"MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres","volume":"6","author":"Pratama","year":"2015","journal-title":"Nat Commun"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500780","article-title":"PU.1 Expression in T Follicular Helper Cells Limits CD40L-Dependent Germinal Center B Cell Development","volume":"195","author":"Awe","year":"2015","journal-title":"J Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.03.024","article-title":"Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone","volume":"34","author":"Kerfoot","year":"2011","journal-title":"Immunity"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.017","article-title":"ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation","volume":"42","author":"Stone","year":"2015","journal-title":"Immunity"},{"key":"B78","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.immuni.2019.06.023","article-title":"A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation","volume":"51","author":"Vacchio","year":"2019","journal-title":"Immunity"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.01.010","article-title":"Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84","volume":"32","author":"Cannons","year":"2010","journal-title":"Immunity"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403023","article-title":"B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance","volume":"194","author":"Wong","year":"2015","journal-title":"J Immunol"},{"key":"B81","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.immuni.2012.05.016","article-title":"The Receptor Ly108 Functions as a SAP Adaptor-Dependent On-Off Switch for T Cell Help to B Cells and NKT Cell Development","volume":"36","author":"Kageyama","year":"2012","journal-title":"Immunity"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.05.009","article-title":"Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages","volume":"29","author":"Nurieva","year":"2008","journal-title":"Immunity"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.06.001","article-title":"A fundamental role for interleukin-21 in the generation of T follicular helper cells","volume":"29","author":"Vogelzang","year":"2008","journal-title":"Immunity"},{"key":"B84","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1111\/imr.12747","article-title":"TFH cells in bystander and cognate interactions with B cells","volume":"288","author":"Wan","year":"2019","journal-title":"Immunol Rev"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.620437\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T05:44:20Z","timestamp":1618379060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.620437\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,14]]},"references-count":84,"alternative-id":["10.3389\/fimmu.2021.620437"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.620437","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,14]]},"article-number":"620437"}}