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

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

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 5

Aberrant expression of key molecules involved in iNKT terminal maturation and effector function.

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Aberrant expression of key molecules involved in iNKT terminal maturatio...
(A–C) Overlaid histograms show expression of T-bet, CD122, RORγt, and ICOS (A) in WT and TSC1KO thymic iNKT cells of different stages; (B) in thymic iNKT cells from WT and TSC1KO mixed BM chimeric mice, as described in Figure 4; (C) and in stage 2 and stage 3 thymic iNKT cells from rapamycin-treated and untreated WT and TSC1KO mice. (D) mRNA levels of indicated molecules in WT and TSC1KO iNKT cells. Expression of indicated mRNA from MACS- and FACS-sorted WT and TSC1KO iNKT cells from freshly isolated thymocytes was quantified by real-time qPCR. Mean ± SEM of triplicates are shown. *P < 0.05; **P < 0.01; ***P < 0.001, Student’s t test. Data shown represent 2 experiments.