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