Ma, Cindy S.Avery, Danielle T.Chan, AnnaBatten, MarcelBustamante, JacintaBoisson-Dupuis, StephanieArkwright, Peter D.Kreins, Alexandra Y.Averbuch, DianaEngelhard, DanMagdorf, KlausMinegishi, YoshiyukiNonoyama, ShigeakiFrench, Martyn A.Choo, SharonSmart, Joanne M.Peake, JaneWong, MelanieGray, PaulCook, Matthew C.Fulcher, David A.Casanova, Jean-LaurentDeenick, Elissa K.Tangye, Stuart G.2022-02-272022-02-272012-04-26Ma, C. S. vd. (2012). "Functional STAT3 deficiency compromises the generation of human T follicular helper cells". Blood, 119(17), 3997-4008.0006-49711528-0020https://doi.org/10.1182/blood-2011-11-392985https://ashpublications.org/blood/article/119/17/3997/29893/Functional-STAT3-deficiency-compromises-thehttp://hdl.handle.net/11452/24673T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12R beta 1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.eninfo:eu-repo/semantics/openAccessHematologyCxc chemokine receptor-5Tyrosine phosphorylationAntibody-responsesTh17 cellsMutationsDifferentiationMycobacterialIl-21IcosBcl6Article0003052829000212-s2.0-84859711557399740081191722403255HematologyHelper Cell; Germinal Center; Interleukin-21Chemokine receptor cxcr5Interleukin 12Interleukin 12 receptor beta1Interleukin 21Protein bcl 6Protein kinase tyk2Stat1 proteinStat3 proteinAdolescentAdultArticleB lymphocyteCD4+ T lymphocyteCell lineCell lineageCell maturationControlled studyGene mutationHelper cellHumanHuman cellIn vitro studyIn vivo studyLymphocyte differentiationPriority journalProtein expression