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iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions
Jinhong Wu, … , Hongbo Chi, Xiao-Ping Zhong
Jinhong Wu, … , Hongbo Chi, Xiao-Ping Zhong
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1685-1698. https://doi.org/10.1172/JCI69780.
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Research Article

iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions

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Abstract

Terminal maturation of invariant NKT (iNKT) cells from stage 2 (CD44+NK1.1–) to stage 3 (CD44+NK1.1+) is accompanied by a functional acquisition of a predominant IFN-γ–producing (iNKT-1) phenotype; however, some cells develop into IL-17–producing iNKT (iNKT-17) cells. iNKT-17 cells are rare and restricted to a CD44+NK1.1– lineage. It is unclear how iNKT terminal maturation is regulated and what factors mediate the predominance of iNKT-1 compared with iNKT-17. The tumor suppressor tuberous sclerosis 1 (TSC1) is an important negative regulator of mTOR signaling, which regulates T cell differentiation, function, and trafficking. Here, we determined that mice lacking TSC1 exhibit a developmental block of iNKT differentiation at stage 2 and skew from a predominantly iNKT-1 population toward a predominantly iNKT-17 population, leading to enhanced airway hypersensitivity. Evaluation of purified iNKT cells revealed that TSC1 promotes T-bet, which regulates iNKT maturation, but downregulates ICOS expression in iNKT cells by inhibiting mTOR complex 1 (mTORC1). Furthermore, mice lacking T-bet exhibited both a terminal maturation defect of iNKT cells and a predominance of iNKT-17 cells, and increased ICOS expression was required for the predominance of iNKT-17 cells in the population of TSC1-deficient iNKT cells. Our data indicate that TSC1-dependent control of mTORC1 is crucial for terminal iNKT maturation and effector lineage decisions, resulting in the predominance of iNKT-1 cells.

Authors

Jinhong Wu, Jialong Yang, Kai Yang, Hongxia Wang, Balachandra Gorentla, Jinwook Shin, Yurong Qiu, Loretta G. Que, W. Michael Foster, Zhenwei Xia, Hongbo Chi, Xiao-Ping Zhong

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Figure 3

Increased airway hyperreactivity, neutrophilic infiltration, and Il17a mRNA levels in the lungs of TSC1-deficient mice.

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Increased airway hyperreactivity, neutrophilic infiltration, and Il17a m...
WT and TSC1KO mice were treated intranasally (i.n.) with 2 μg α-GalCer in 50 μl PBS. Twenty-four hours later, changes in airway resistance to succeeding doses of aerosolized methacholine were assessed. Mice were then euthanized for collection of BAL fluid, and lung tissues were harvested for histologic examination. (A) Airway response to methacholine. AvgRT, average total pulmonary resistance. (B) Total leukocyte numbers in BAL fluid. (C) Percentages of macrophages and neutrophils in the BAL fluid. (D) Representative H&E staining of WT and TSC1KO BAL fluid infiltrates. Arrows and arrowheads represent neutrophils and macrophages, respectively. (E) Enhanced interstitial infiltration in TSC1KO lungs. Representative H&E staining of lung thin sections is shown. (F) mRNA levels of Il17a (increased) and Ifng (decreased) in the lungs of TSC1KO mice 5 hours after α-GalCer treatment. (G) Neutrophil numbers in the lungs after S. pneumoniae infection. Ctrl, uninfected; Infect, infected. (H) mRNA levels of indicated cytokines in iNKT cells isolated from lungs after S. pneumoniae infection. *P < 0.05; **P < 0.01; ***P < 0.001, 2-way ANOVA (A); Student’s t test (B–H). Data are representative of 2 independent experiments with 4 mice (A–F) and 5 mice (G and H) per group in each experiment. Original magnification, ×400 (D); ×200 (E).

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