TSC1 is critical for iNKT-cell terminal maturation and controls iNKT-1/17 balance (IRM7P.490)

Abstract

Abstract iNKT-cells terminal maturation from CD44+NK1.1- stage 2 to CD44+NK1.1+ stage 3 is accompanied by functional acquisition of predominant IFNγ-producing (iNKT-1) but not IL-17-producing (iNKT-17) capability. iNKT-17-cells are rare and restricted to the CD44+NK1.1- subset. The mechanisms that control iNKT terminal maturation and predominance of iNKT-1 over iNKT-17 remain poorly understood. The tumor suppressor tuberous sclerosis 1 (TSC1) is an important negative regulator of mTOR signaling. We demonstrate here that deficiency of the TSC1 causes iNKT-cell developmental block at stage 2 and functional alteration from iNKT-1 predominance to iNKT-17 predominance, leading to enhanced airway hypersensitivity. TSC1 promotes T-bet but downregulates ICOS expression in iNKT-cells by inhibiting mTOR complex 1. Decreased T-bet contributes to both terminal maturation defect and iNKT-17 predominance over iNKT-1 while increased ICOS expression is required for iNKT-17 predominance in TSC1-deficient iNKT-cells. Thus, TSC1and its proper control of mTORC1 are crucial for iNKT-cell terminal maturation and effector lineage decision for iNKT-1 predominance over iNKT-17.