Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF | Corrigendum | Expression of Concern
Research Article

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

  • Text
  • PDF
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

×

Figure 6

TSC1 promotes T-bet expression to establish iNKT–IFN-γ predominance over iNKT-17 and for efficient iNKT terminal maturation.

Options: View larger image (or click on image) Download as PowerPoint
TSC1 promotes T-bet expression to establish iNKT–IFN-γ predominance over...
(A) iNKT cell staining of WT and T-betKO iNKT cells in thymi. (B) IFN-γ and IL-17 staining in WT and T-betKO iNKT cells after P + I stimulation for 5 hours or α-GalCer for 72 hours (mean ± SEM from 4 pairs of mice). (C) ICOS and RORγt staining in WT and T-betKO iNKT cells. (D) Decreased Icos mRNA levels (mean ± SEM) in iNKT hybridoma (3C3) retrovirally transduced with T-bet. (E and F) Overexpression of T-bet promoted IFN-γ but inhibited IL-17 production by iNKT cells. WT and TSC1KO thymocytes were stimulated with α-GalCer in vitro and infected with GFP–expressing (vector) or GFP+T-bet–expressing (T-bet) retrovirus. Two days after infection and with the last 5-hour treatment with P + I, iNKT cells and cytokines were stained. (E) GFP expression in iNKT cells and IFN-γ and IL-17A expression in GFP+ iNKT cells. (F) IL-17A to IFN-γ ratios in GFP+-transduced iNKT cells (mean ± SEM). (G) Overexpression of T-bet partially restored TSC1KO iNKT terminal maturation. WT and TSC1KO BM cells, transduced with retrovirus expressing GFP or GFP+T-bet, were i.v. injected into sublethally irradiated Tcra–/– mice. Recipient mice were analyzed 6 to 8 weeks after reconstitution. Contour plots show CD44 and NK1.1 expression on GFP+ and GFP– live-gated CD1dTet+TCRβ+ iNKT cells. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA (F) and Student’s t test (B and D). Data are representative of 3 independent experiments.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts