mTORC2 regulates multiple aspects of NKT-cell development and function (original) (raw)
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The Journal of Immunology, 2014
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...
Invariant NKT cells inhibit development of the Th17 lineage
Proceedings of the National Academy of Sciences of the United States of America, 2009
T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th(1) and Th(2) responses. Recently, a new subset of CD4(+) T helper cells, called Th(17), was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4(+) T cells. Transferred naïve CD25(-)CD62L(+) CD4(+) T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th(17) differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th(17) lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-gamma in the...
PLoS Biology, 2013
Natural killer T (NKT) cell development depends on recognition of self-glycolipids via their semi-invariant Va14i-TCR. However, to what extent TCR-mediated signals determine identity and function of mature NKT cells remains incompletely understood. To address this issue, we developed a mouse strain allowing conditional Va14i-TCR expression from within the endogenous Tcra locus. We demonstrate that naïve T cells are activated upon replacement of their endogenous TCR repertoire with Va14i-restricted TCRs, but they do not differentiate into NKT cells. On the other hand, induced TCR ablation on mature NKT cells did not affect their lineage identity, homeostasis, or innate rapid cytokine secretion abilities. We therefore propose that peripheral NKT cells become unresponsive to and thus are independent of their autoreactive TCR.
Journal of Cellular Physiology, 2019
The mammalian target of rapamycin (mTOR) is a member of the evolutionary phosphatidylinositol kinase‐related kinases (PIKKs). mTOR plays a pivotal role in the regulation of diverse aspects of cellular physiology such as body metabolism, cell growth, protein synthesis, cell size, autophagy, and cell differentiation. Immunologically, mTOR has a fundamental part in controlling and shaping diverse functions of innate and adaptive immune cells, in particular, T‐cell subsets differentiation, survival, and metabolic reprogramming to ultimately regulate the fate of diverse immune cell types. Researchers report that rapamycin, a selective mTOR inhibitor, and immunosuppressive agent, has surprising immunostimulatory effects on inducing both quantitative and qualitative aspects of virus‐specific memory CD8+ T‐cells differentiation and homeostasis in a T‐cell‐intrinsic manner. The mTOR signaling pathway also plays a critical role in dictating the outcome of regulatory T cells (Treg), T helper 1...
T-bet Regulates the Terminal Maturation and Homeostasis of NK and Vα14i NKT Cells
Immunity, 2004
function, and major recent advances have been made in understanding their function (Arase et al., 2002; Faure and Immunology Seaman, 2000). Terminal maturation is accompanied by high expression of CD11b and CD43 together with opti-Division of Biology and Medicine, Box G-B Brown University mal cytolytic function and IFN-␥ production (Kim et al., 2002; Yokoyama et al., 2003). Mature NK cells are be-Providence, Rhode Island 02912 lieved to be terminally differentiated and, once in the periphery, static in terms of proliferative capacity until challenge with pathogen. Radio-resistant BM cells pro-Summary ducing IL-15 are critical for NK cell development and homeostasis (Kennedy et al., 2000; Ranson et al., Natural killer (NK) and CD1d-restricted V␣14i natural 2003b). Other critical factors in the microenvironment killer T (NKT) cells play a critical early role in host deinclude IL-7 and cell-cell contact between BM stromal fense. Here we show that mice with a targeted deletion cells and developing NK cells via lymphotoxin receptors of T-bet, a T-box transcription factor required for Th1 and cell surface lymphotoxin, respectively (Colucci et cell differentiation, have a profound, stem cell-intrinsic al., 2003). Several transcription factors have been identidefect in their ability to generate mature NK and V␣14i fied that are important for NK cell development. IRF-1 NKT cells. Both cell types fail to complete normal teracts in a stem cell-extrinsic manner, explained by the minal maturation and are present in decreased numdefect in IL-15 production in IRF-1 Ϫ/Ϫ BM (Ogasawara bers in peripheral lymphoid organs of T-bet Ϫ/Ϫ mice. et al., 1998). Other factors such as IRF-2, ID2, Ets1, T-bet expression is regulated during NK cell differenti-MEF, and PU.1 regulate NK development in a stem cellation by NK-activating receptors and cytokines known intrinsic manner (Barton et al., 1998; Colucci et al., 2001; to control NK development and effector function. Our Lacorazza et al., 2002; Lohoff et al., 2000; Yokota et results identify T-bet as a key factor in the terminal al., 1999), and mice lacking these transcription factors maturation and peripheral homeostasis of NK and generally have developmental defects in multiple lym-V␣14i NKT cells. phoid lineages. However, the molecular mechanisms involved and the precise stage of development affected by loss of these factors remains unclear. Introduction NKT cells possess properties of both T cells and NK The innate immune system plays a critical early role in cells in that they coexpress a T cell receptor (TCR) and a host defense in response to viruses, bacteria, and tumor panoply of receptors of the NK lineage, including NK1.1, cells. Two of its cell lineages, NK and NKT cells, do not NKG2D, and members of the Ly-49 family (Bendelac et require prior sensitization for effector function and are al., 1997; Ho et al., 2002). Recent progress has been vital both for initially combating infection and for subsemade in identifying their developmental intermediates. quently activating the adaptive immune system by phys-The majority of NKT cells contain an invariant TCR reical interaction with dendritic cells and by the secretion arrangement of V␣14 to J␣18 and are reactive to the of immunoregulatory cytokines. glycolipid ␣-galactosylceramide (␣GalCer) presented on Although some progress has been made in identifying CD1d, so-called V␣14 invariant (V␣14i ) NKT cells (Kroand understanding the in vivo stages of NK cell lineage nenberg and Gapin, 2002). NKT cells develop from CD4 ϩ CD8 ϩ double-positive (DP) V␣14-J␣18 TCR ϩ thymic precursors which then upregulate CD44 expression;