Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

J Immunol. 2014 Aug 15;193(4):1759-65. doi: 10.4049/jimmunol.1400769. Epub 2014 Jul 11.

Abstract

Invariant NKT (iNKT) cells play critical roles in bridging innate and adaptive immunity. The Raptor containing mTOR complex 1 (mTORC1) has been well documented to control peripheral CD4 or CD8 T cell effector or memory differentiation. However, the role of mTORC1 in iNKT cell development and function remains largely unknown. By using mice with T cell-restricted deletion of Raptor, we show that mTORC1 is selectively required for iNKT but not for conventional T cell development. Indeed, Raptor-deficient iNKT cells are mostly blocked at thymic stage 1-2, resulting in a dramatic decrease of terminal differentiation into stage 3 and severe reduction of peripheral iNKT cells. Moreover, residual iNKT cells in Raptor knockout mice are impaired in their rapid cytokine production upon αGalcer challenge. Bone marrow chimera studies demonstrate that mTORC1 controls iNKT differentiation in a cell-intrinsic manner. Collectively, our data provide the genetic evidence that iNKT cell development and effector functions are under the control of mTORC1 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • Cytokines / biosynthesis
  • Immunologic Memory
  • Interferon-gamma / biosynthesis
  • Lectins, C-Type / biosynthesis
  • Lymphocyte Activation / immunology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / genetics*
  • Natural Killer T-Cells / cytology*
  • Natural Killer T-Cells / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology
  • TOR Serine-Threonine Kinases / genetics*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Cytokines
  • Lectins, C-Type
  • Multiprotein Complexes
  • Receptors, Antigen, T-Cell, gamma-delta
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1