First published November 1, 2017 - More info
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.
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
Original citation: J Clin Invest. 2014;124(4):1685–1698. https://doi.org/10.1172/JCI69780
Citation for this expression of concern: J Clin Invest. 2017;127(11):4216. https://doi.org/10.1172/JCI98066
An investigative committee at Duke University recently reported that a research technician in the animal pulmonary physiology laboratory fabricated and/or falsified flexiVent data reported in Figure 3A of this paper. The Editorial Board is issuing this Expression of Concern to alert readers to these problems. The Editors have requested that the experiments in question be repeated by the authors and resubmitted to the Journal. We will inform our readers of the outcome after the data have been evaluated.
See the related article at iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.