Ma, Cindy S.Wong, NatalieRao, GeethaNguyen, AkiraAvery, Danielle T.Payne, KathrynTorpy, JamesO'Young, PatrickDeenick, ElissaBustamante, JacintaPuel, AnneOkada, SatoshiKobayashi, MasaoMartinez-Barricarte, RubenElliott, MichaelEl Baghdadi, JamilaMinegishi, YoshiyukiBousfiha, AzizRobertson, NicHambleton, SophieArkwright, Peter D.French, MartynBlincoe, Annaliesse K.Hsu, PeterCampbell, Dianne E.Stormon, Michael O.Wong, MelanieAdelstein, StephenFulcher, David A.Cook, Matthew C.Stepensky, PolinaBoztuğ, KaanBeier, Ritaİkincioğulları, AydanZiegler, John B.Gray, PaulPicard, CapucineBoisson-Dupuis, StephanieTri Giang, PhanGrimbacher, BodoWarnatz, KlausHolland, Steven M.Uzel, GülbüCasanova, Jean-LaurentTangye, Stuart G.2022-09-272022-09-272016-07-25Ma, C. S. vd. (2016). "Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4(+) T cells into distinct effector subsets". Journal of Experimental Medicine, 213(8), 1589-1608.0022-10071540-9538https://doi.org/10.1084/jem.20151467https://rupress.org/jem/article/213/8/1589/42083/Unique-and-shared-signaling-pathways-cooperate-tohttp://hdl.handle.net/11452/28838Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12R beta 1/TYK2 and IFN-gamma R/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12R beta 1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.eninfo:eu-repo/semantics/openAccessHyper-ige syndromeChronic mucocutaneous candidiasisFollicular-helper-cellsCommon variable immunodeficiencyEssential modulator mutationAntibody-responsesEctodermal dysplasiaIL-10 productionIcos deficiencyBCL6 expressionAntigens, differentiationCell differentiationFemaleHumansInterleukin-10MaleMutationSTAT1 transcription factorSTAT3 transcription factorTh1 cellsTh17 cellsTh2 cellsArticle0003808512000152-s2.0-8498293827615891608213827401342ImmunologyMedicine, research & experimentalHelper Cell; Germinal Center; Tfh CellCD4 antigenGamma interferonGamma interferon receptorL kappa B kinase gammaInterleukin 10Interleukin 12 receptor beta1Interleukin 21Interleukin 21 receptorProtein kinase TYK2STAT1 proteinSTAT3 proteinSTAT4 proteinSTAT6 proteinDifferentiation antigenIL10 protein, mouseInterleukin 10STAT1 protein, humanHumanArticleCD4+ T lymphocyteCell subpopulationControlled studyCytokine releaseEffector cellGain of function mutationGeneHumanHuman cellHumoral immunityImmune deficiencyImmunomodulationImmunoregulationIn vitro studyInfection sensitivityIntracellular signalingLymphocyte differentiationPriority journalProtein phosphorylationSTAT1 geneSTAT3 geneTh0 cellTh1 cellTh17 cellTh2 cellCell differentiationCytologyFemaleGeneticsImmunologyMaleMutation