NKT Cells Contribute to the Control of Microbial Infections.
Vogt Stefan,Mattner Jochen
Frontiers in cellular and infection microbiology
Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.
Functions of CD1d-Restricted Invariant Natural Killer T Cells in Antimicrobial Immunity and Potential Applications for Infection Control.
Kinjo Yuki,Takatsuka Shogo,Kitano Naoki,Kawakubo Shun,Abe Masahiro,Ueno Keigo,Miyazaki Yoshitsugu
Frontiers in immunology
CD1d-restricted invariant natural killer T (NKT) cells are innate-type lymphocytes that express a T-cell receptor (TCR) containing an invariant α chain encoded by the gene in mice and gene in humans. These NKT cells recognize endogenous, microbial, and synthetic glycolipid antigens presented by the major histocompatibility complex (MHC) class I-like molecule CD1d. Upon TCR stimulation by glycolipid antigens, NKT cells rapidly produce large amounts of cytokines, including interferon-γ (IFNγ) and interleukin-4 (IL-4). Activated NKT cells contribute to host protection against a broad spectrum of microbial pathogens, and glycolipid-mediated stimulation of NKT cells ameliorates many microbial infections by augmenting innate and acquired immunity. In some cases, however, antigen-activated NKT cells exacerbate microbial infections by promoting pathogenic inflammation. Therefore, it is important to identify appropriate microbial targets for the application of NKT cell activation as a treatment or vaccine adjuvant. Many studies have found that NKT cell activation induces potent adjuvant activities promoting protective vaccine effects. In this review, we summarize the functions of CD1d-restricted NKT cells in immune responses against microbial pathogens and describe the potential applications of glycolipid-mediated NKT cell activation for preventing and controlling microbial infections.
Calcium signals regulate the functional differentiation of thymic iNKT cells.
Zhao Meng,Quintana Ariel,Zhang Chen,Andreyev Alexander Y,Kiosses William,Kuwana Tomomi,Murphy Anne,Hogan Patrick G,Kronenberg Mitchell
The EMBO journal
How natural or innate-like lymphocytes generate the capacity to produce IL-4 and other cytokines characteristic of type 2 immunity remains unknown. Invariant natural killer T (iNKT) cells differentiate in the thymus into NKT1, NKT2, and NKT17 subsets, similar to mature, peripheral CD4 T helper cells. The mechanism for this differentiation was not fully understood. Here, we show that NKT2 cells required higher and prolonged calcium (Ca ) signals and continuing activity of the calcium release-activated calcium (CRAC) channel, than their NKT1 counterparts. The sustained Ca entry via CRAC pathway in NKT2 cells was apparently mediated by ORAI and controlled in part by the large mitochondrial Ca uptake. Unique properties of mitochondria in NKT2 cells, including high activity of oxidative phosphorylation, may regulate mitochondrial Ca buffering in NKT2 cells. In addition, the low Ca extrusion rate may also contribute to the higher Ca level in NKT2 cells. Altogether, we identified ORAI-dependent Ca signaling connected with mitochondria and cellular metabolism, as a central regulatory pathway for the differentiation of NKT2 cells.