iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.
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.
Duke Scholars
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- 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
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
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