title: iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.
abstract: 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.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Wu
authors.forename: Jialong
authors.initials: J
authors.lastname: Yang
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.forename: Balachandra
authors.initials: B
authors.lastname: Gorentla
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.forename: Yurong
authors.initials: Y
authors.lastname: Qiu
authors.forename: Loretta G
authors.initials: LG
authors.lastname: Que
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Xia
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D007113:Immunity, Innate; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D046912:Multiprotein Complexes; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases