{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:44:09Z","timestamp":1792140249461,"version":"4.4.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR25335\/NER\/95"],"award-info":[{"award-number":["BT\/PR25335\/NER\/95"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunol Cell Biol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Follicular helper T (Tfh) cells orchestrate germinal center (GC) derived humoral immunity by providing essential help to B cells. Despite their key role in humoral immunity, the metabolic cues that shape Tfh cell differentiation and functions in humans remain poorly understood. Here, using a human ex\u00a0vivo Tfh cell differentiation model, we investigated the metabolic requirements of Tfh cell development and function through targeted metabolic perturbation of glycolysis and fatty acid metabolism, transcriptomic analyses, and metabolic rescue experiments. Unexpectedly, early glycolytic inhibition enhanced Tfh cell differentiation but markedly impaired function, including reduced IL\u201021 production and diminished B\u2010cell help. Transcriptomic and metabolic analyses revealed that glycolytic inhibition was accompanied by suppression of fatty acid metabolism. Consistently, independent inhibition of fatty acid synthesis or oxidation suppressed Tfh cell help functions, including IL\u201021 and IFN\u2010\u03b3 production, as well as B\u2010cell help potential. Interestingly, acetate supplementation partially restored IFN\u2010\u03b3 secretion in glycolysis\u2010inhibited conditions, but not IL\u201021, indicating limited metabolic compensation. Together, these findings reveal distinct metabolic requirements for Tfh cell differentiation and function and identify glycolysis\u2010dependent fatty acid metabolism as an important determinant of human Tfh cell functional competence. This metabolic crosstalk provides new insight into the regulation of Tfh cells and Tfh\u2010driven humoral immunity in vaccination and autoimmunity.<\/jats:p>","DOI":"10.1111\/imcb.70166","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:47:53Z","timestamp":1792136873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glycolysis\u2010Dependent Fatty Acid Metabolism Supports Human Tfh Cell Function"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3690-1399","authenticated-orcid":false,"given":"Someshwar Nath","family":"Jha","sequence":"first","affiliation":[{"name":"National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhushan","family":"Nikam","sequence":"additional","affiliation":[{"name":"National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivekananda","family":"Barik","sequence":"additional","affiliation":[{"name":"National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuska","family":"Khatua","sequence":"additional","affiliation":[{"name":"National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Jena","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa","family":"Sachan","sequence":"additional","affiliation":[{"name":"National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamuni","family":"Swain","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Coshic","sequence":"additional","affiliation":[{"name":"All India Institute of Medical Sciences  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9913-4241","authenticated-orcid":false,"given":"Sunil K.","family":"Raghav","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences  Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9433-8448","authenticated-orcid":false,"given":"Nimesh","family":"Gupta","sequence":"additional","affiliation":[{"name":"National Institute of Immunology  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.immuni.2014.10.004","article-title":"T Follicular Helper Cell Differentiation, Function, and Roles in Disease","volume":"41","author":"Crotty S.","year":"2014","journal-title":"Immunity"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1126\/science.1175870","article-title":"Bcl6 and Blimp\u20101 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation","volume":"325","author":"Johnston R. J.","year":"2009","journal-title":"Science"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"239","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 E. L.","year":"2015","journal-title":"Immunity"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.4049\/jimmunol.1003650","article-title":"Strength of TCR\u2010Peptide\/MHC Interactions and In\u00a0Vivo T Cell Responses","volume":"186","author":"Corse E.","year":"2011","journal-title":"Journal of Immunology"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.immuni.2009.04.014","article-title":"The mTOR Kinase Differentially Regulates Effector and Regulatory T Cell Lineage Commitment","volume":"30","author":"Delgoffe G. M.","year":"2009","journal-title":"Immunity"},{"issue":"11","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.3390\/cells8111450","article-title":"HIF1alpha\u2010Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells","volume":"8","author":"Dong L.","year":"2019","journal-title":"Cells"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/icb.2013.62","article-title":"Priming of T Follicular Helper Cells by Dendritic Cells","volume":"92","author":"Ballesteros\u2010Tato A.","year":"2014","journal-title":"Immunology and Cell Biology"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"540","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 H.","year":"2016","journal-title":"Immunity"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.immuni.2015.08.017","article-title":"The Interleukin\u20102\u2010mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells","volume":"43","author":"Ray J. P.","year":"2015","journal-title":"Immunity"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1084\/jem.20190337","article-title":"The E3 Ligase VHL Promotes Follicular Helper T Cell Differentiation via Glycolytic\u2010Epigenetic Control","volume":"216","author":"Zhu Y.","year":"2019","journal-title":"Journal of Experimental Medicine"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01973","article-title":"Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis","volume":"9","author":"Abboud G.","year":"2018","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"4369","DOI":"10.1038\/s41467-018-06686-0","article-title":"Inhibition of Glucose Metabolism Selectively Targets Autoreactive Follicular Helper T Cells","volume":"9","author":"Choi S. C.","year":"2018","journal-title":"Nature Communications"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.imlet.2022.03.008","article-title":"Metabolic Regulation of Follicular Helper T Cell Differentiation in a Mouse Model of Lupus","volume":"247","author":"Zou X.","year":"2022","journal-title":"Immunology Letters"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1038\/s41467-021-23220-x","article-title":"The Metabolic Hormone Leptin Promotes the Function of T(FH) Cells and Supports Vaccine Responses","volume":"12","author":"Deng J.","year":"2021","journal-title":"Nature Communications"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1172\/JCI76238","article-title":"Follicular Helper T Cell Signature in Type 1 Diabetes","volume":"125","author":"Kenefeck R.","year":"2015","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1038\/s41590-020-0744-z","article-title":"Follicular Helper T Cell Profiles Predict Response to Costimulation Blockade in Type 1 Diabetes","volume":"21","author":"Edner N. M.","year":"2020","journal-title":"Nature Immunology"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/icb.2009.64","article-title":"Early Commitment of Naive Human CD4(+) T Cells to the T Follicular Helper (T(FH)) Cell Lineage Is Induced by IL\u201012","volume":"87","author":"Ma C. S.","year":"2009","journal-title":"Immunology and Cell Biology"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 Mediates the Development of T Follicular Helper Cells","volume":"325","author":"Nurieva R. 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I.","year":"2014","journal-title":"Genome Biology"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex Heatmaps Reveal Patterns and Correlations in Multidimensional Genomic Data","volume":"32","author":"Gu Z.","year":"2016","journal-title":"Bioinformatics"},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.chembiol.2019.06.005","article-title":"Inhibition of Glucose Transporters and Glutaminase Synergistically Impairs Tumor Cell Growth","volume":"26","author":"Reckzeh E. S.","year":"2019","journal-title":"Cell Chemical Biology"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nature12910","article-title":"Transcription Factor Achaete\u2010Scute Homologue 2 Initiates Follicular T\u2010Helper\u2010Cell Development","volume":"507","author":"Liu X.","year":"2014","journal-title":"Nature"},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"586","DOI":"10.4049\/jimmunol.1701000","article-title":"Foxp1 Negatively Regulates T Follicular Helper Cell Differentiation and Germinal Center Responses by Controlling Cell Migration and CTLA\u20104","volume":"200","author":"Shi B.","year":"2018","journal-title":"Journal of Immunology"},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000270","article-title":"Foxp1 Is Critical for the Maintenance of Regulatory T\u2010Cell Homeostasis and Suppressive Function","volume":"17","author":"Ren J.","year":"2019","journal-title":"PLoS Biology"},{"key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/ni.2890","article-title":"The Transcription Factor Foxp1 Is a Critical Negative Regulator of the Differentiation of Follicular Helper T Cells","volume":"15","author":"Wang H.","year":"2014","journal-title":"Nature Immunology"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.immuni.2015.01.013","article-title":"The Transcription Factor KLF2 Restrains CD4(+) T Follicular Helper Cell Differentiation","volume":"42","author":"Lee J. Y.","year":"2015","journal-title":"Immunity"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.7554\/eLife.88204","article-title":"Transmembrane Protein CD69 Acts as an S1PR1 Agonist","volume":"12","author":"Chen H.","year":"2023","journal-title":"eLife"},{"key":"e_1_2_10_39_1","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2017.1283468","article-title":"CD69 Is a Direct HIF\u20101alpha Target Gene in Hypoxia as a Mechanism Enhancing Expression on Tumor\u2010Infiltrating T Lymphocytes","volume":"6","author":"Labiano S.","year":"2017","journal-title":"Oncoimmunology"},{"key":"e_1_2_10_40_1","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/nm.3704","article-title":"De Novo Fatty Acid Synthesis Controls the Fate Between Regulatory T and T Helper 17 Cells","volume":"20","author":"Berod L.","year":"2014","journal-title":"Nature Medicine"},{"key":"e_1_2_10_41_1","doi-asserted-by":"crossref","first-page":"8552","DOI":"10.1073\/pnas.0603115103","article-title":"Liver\u2010Specific Deletion of Acetyl\u2010CoA Carboxylase 1 Reduces Hepatic Triglyceride Accumulation Without Affecting Glucose Homeostasis","volume":"103","author":"Mao J.","year":"2006","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_10_42_1","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s11745-014-3911-x","article-title":"Acetate Treatment Increases Fatty Acid Content in LPS\u2010Stimulated BV2 Microglia","volume":"49","author":"Bhatt D. P.","year":"2014","journal-title":"Lipids"},{"key":"e_1_2_10_43_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/ni.2912","article-title":"The E3 Ubiquitin Ligase Itch Is Required for the Differentiation of Follicular Helper T Cells","volume":"15","author":"Xiao N.","year":"2014","journal-title":"Nature Immunology"},{"key":"e_1_2_10_44_1","doi-asserted-by":"crossref","first-page":"447","DOI":"10.4049\/immunohorizons.1800079","article-title":"Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages","volume":"3","author":"Dekker J. D.","year":"2019","journal-title":"Immunohorizons"},{"key":"e_1_2_10_45_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2023.104795","article-title":"The Transcription Factor Foxp1 Regulates Aerobic Glycolysis in Adipocytes and Myocytes","volume":"299","author":"Ma H.","year":"2023","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_10_46_1","article-title":"Blood Molecular Markers Associated With COVID\u201019 Immunopathology and Multi\u2010Organ Damage","volume":"39","author":"Chen Y. 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W.","year":"1989","journal-title":"Metabolism"},{"key":"e_1_2_10_51_1","first-page":"E8027","article-title":"DUSP6 Mediates T Cell Receptor\u2010Engaged Glycolysis and Restrains T(FH) Cell Differentiation","volume":"115","author":"Hsu W. C.","year":"2018","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_10_52_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2025.116600","article-title":"Glycolysis Inhibition Functionally Reprograms T Follicular Helper Cells and Reverses Lupus","volume":"44","author":"Choi S. C.","year":"2025","journal-title":"Cell Reports"},{"key":"e_1_2_10_53_1","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1016\/j.celrep.2019.04.022","article-title":"Acetate Promotes T Cell Effector Function During Glucose Restriction","volume":"27","author":"Qiu J.","year":"2019","journal-title":"Cell Reports"},{"key":"e_1_2_10_54_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biochi.2021.06.017","article-title":"Cellular Binding and Uptake of Fluorescent Glucose Analogs 2\u2010NBDG and 6\u2010NBDG Occurs Independent of Membrane Glucose Transporters","volume":"190","author":"Hamilton K. E.","year":"2021","journal-title":"Biochimie"}],"container-title":["Immunology &amp; Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imcb.70166","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/imcb.70166","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imcb.70166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:48:00Z","timestamp":1792136880000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imcb.70166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,16]]},"references-count":53,"alternative-id":["10.1111\/imcb.70166"],"URL":"https:\/\/doi.org\/10.1111\/imcb.70166","archive":["Portico"],"relation":{},"ISSN":["0818-9641","1440-1711"],"issn-type":[{"value":"0818-9641","type":"print"},{"value":"1440-1711","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,16]]},"assertion":[{"value":"2026-04-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"imcb.70166"}}