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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • April 2014

Published In

Volume / Issue

  • 124 / 4

Start / End Page

  • 1685 - 1698

PubMed ID

  • 24614103

Pubmed Central ID

  • 24614103

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI69780

Language

  • eng

Conference Location

  • United States