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Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets

Lookup NU author(s): Nicholas Robertson, Professor Sophie HambletonORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).


Naive 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.

Publication metadata

Author(s): Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, Torpy J, O'Young P, Deenick E, Bustamante J, Puel A, Okada S, Kobayashi M, Martinez-Barricarte R, Elliott M, Kilic SS, El Baghdadi J, Minegishi Y, Bousfiha A, Robertson N, Hambleton S, Arkwright PD, French M, Blincoe AK, Hsu P, Campbell DE, Stormon MO, Wong M, Adelstein S, Fulcher DA, Cook MC, Stepensky P, Boztug K, Beier R, Ikinciogullari A, Ziegler JB, Gray P, Picard C, Boisson-Dupuis S, Phan TG, Grimbacher B, Warnatz K, Holland SM, Uzel G, Casanova JL, Tangye SG

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2016

Volume: 213

Issue: 8

Pages: 1589-1608

Print publication date: 25/07/2016

Online publication date: 11/07/2016

Acceptance date: 13/05/2016

Date deposited: 04/10/2016

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press


DOI: 10.1084/jem.20151467


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Funder referenceFunder name
Fulbright Commission
01EO1303German Federal Ministry of Education and Research (BMBF)
1016953National Health and Medical Research Council (NHM RC) of Australia
1027400National Health and Medical Research Council (NHM RC) of Australia
1066694National Health and Medical Research Council (NHM RC) of Australia
1004632National Health and Medical Research Council (NHM RC) of Australia
1042925NHMRC of Australia
596813National Health and Medical Research Council (NHM RC) of Australia
5UL1RR024143Rockefeller University Center for 541 Clinical and Translational science