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

Publication ,  Journal Article
Wu, J; Yang, J; Yang, K; Wang, H; Gorentla, B; Shin, J; Qiu, Y; Que, LG; Foster, WM; Xia, Z; Chi, H; Zhong, X-P
Published in: J Clin Invest
April 2014

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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

April 2014

Volume

124

Issue

4

Start / End Page

1685 / 1698

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • T-Box Domain Proteins
  • Signal Transduction
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Natural Killer T-Cells
  • Multiprotein Complexes
  • Models, Biological
  • Mice, Transgenic
 

Citation

APA
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MLA
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Wu, J., Yang, J., Yang, K., Wang, H., Gorentla, B., Shin, J., … Zhong, X.-P. (2014). iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest, 124(4), 1685–1698. https://doi.org/10.1172/JCI69780
Wu, Jinhong, Jialong Yang, Kai Yang, Hongxia Wang, Balachandra Gorentla, Jinwook Shin, Yurong Qiu, et al. “iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.J Clin Invest 124, no. 4 (April 2014): 1685–98. https://doi.org/10.1172/JCI69780.
Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, et al. iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest. 2014 Apr;124(4):1685–98.
Wu, Jinhong, et al. “iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.J Clin Invest, vol. 124, no. 4, Apr. 2014, pp. 1685–98. Pubmed, doi:10.1172/JCI69780.
Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, Qiu Y, Que LG, Foster WM, Xia Z, Chi H, Zhong X-P. iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest. 2014 Apr;124(4):1685–1698.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

April 2014

Volume

124

Issue

4

Start / End Page

1685 / 1698

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • T-Box Domain Proteins
  • Signal Transduction
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Natural Killer T-Cells
  • Multiprotein Complexes
  • Models, Biological
  • Mice, Transgenic