Regulation of the Induction and Function of Cytotoxic T Lymphocytes by Natural Killer T Cell

Cytotoxic T lymphocytes (CTLs) play a crucial role in the infections and the antitumor immunity. Induction and activation of antigen-specific CTLs is an important strategy in immunotherapy for various diseases, and several researchers have focused on the modulation of CTL induction and function. Natural killer T (NKT) cells are an important focus area of researchers studying immunomodulatory responses to tumors and infectious diseases. CD1d-restricted NKT cells consist of type I NKT cells and type II NKT cells. -galactosylceramide (-GalCer)-activated type I NKT cells secrete both Th1 (e.g., IFN-) and Th2 cytokines, affect the expression of costimulatory molecules in immune cells, and regulate the host immune system. Type II NKT cells, however, are stimulated by sulfatide, a self-glycolipid derived from myelin, and play an immunosuppressive role in animal model of autoimmune diseases. CTL generation, activation, and suppression are strongly affected by activated type I and type II NKT cells. Thus, the regulation of these NKT cells leads to the modification of CTL function. CTLs contribute to antimicrobial responses, antitumor immune and autoimmune responses. Understanding the role of NKT cells in the regulation of CTL generation, activation, and suppression enable the development of novel treatment strategies for these diseases.

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Invariant Natural Killer T-Cells and Total CD1d Restricted Cells Differentially Influence Lipid Metabolism and Atherosclerosis in Low Density Receptor Deficient Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20184566 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4566

Author(s):

Paul A. VanderLaan ◽

Catherine A. Reardon ◽

Veneracion G. Cabana ◽

Chyung-Ru Wang ◽

Godfrey S. Getz

Keyword(s):

Lipid Metabolism ◽

Natural Killer ◽

Plasma Lipids ◽

Plasma Cholesterol ◽

Atherosclerotic Lesion ◽

Nkt Cells ◽

Type I ◽

Type Ii ◽

Inkt Cells ◽

Natural Killer T

Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR−/−) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in Jα18−/−LDLR−/− mice led to an increase in plasma cholesterol levels in female mice. Transgenic Vα14tg/LDLR−/− mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells.

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Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716669115 ◽

2018 ◽

Vol 115 (6) ◽

pp. E1204-E1213 ◽

Cited By ~ 13

Author(s):

Srinivasan Sundararaj ◽

Jingjing Zhang ◽

S. Harsha Krovi ◽

Romain Bedel ◽

Kathryn D. Tuttle ◽

...

Keyword(s):

T Cell ◽

Natural Killer ◽

Acyl Chain ◽

Nkt Cells ◽

Mouse Strains ◽

Type I ◽

Receptor Repertoire ◽

Acyl Chains ◽

And Function ◽

Natural Killer T

MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 diversity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in CD1D1−/− mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of α-galactosylceramide revealed that its A′-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells.

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Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases

Clinical Microbiology Reviews ◽

10.1128/cmr.00232-20 ◽

2020 ◽

Vol 34 (2) ◽

pp. e00232-20

Author(s):

Nicolás M. S. Gálvez ◽

Karen Bohmwald ◽

Gaspar A. Pacheco ◽

Catalina A. Andrade ◽

Leandro J. Carreño ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Infectious Diseases ◽

Natural Killer ◽

Nkt Cells ◽

Interleukin 4 ◽

Type I ◽

Inkt Cells ◽

Class I Mhc ◽

Natural Killer T

SUMMARYThe immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.

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Dynamic changes of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and natural killer T (NKT) cells in patients with acute hepatitis B infection

Virology Journal ◽

10.1186/1743-422x-8-199 ◽

2011 ◽

Vol 8 (1) ◽

Cited By ~ 23

Author(s):

Jun Li ◽

Yaping Han ◽

Ke Jin ◽

Yufeng Wan ◽

Shixia Wang ◽

...

Keyword(s):

T Lymphocytes ◽

Hepatitis B ◽

Acute Hepatitis ◽

Nk Cells ◽

Natural Killer ◽

Cytotoxic T Lymphocytes ◽

Nkt Cells ◽

Hepatitis B Infection ◽

Dynamic Changes ◽

Acute Hepatitis B

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Role of Natural Killer T (NKT) Cells in Type II Diabetes-Induced Vascular Injuries

Medical Science Monitor ◽

10.12659/msm.912446 ◽

2018 ◽

Vol 24 ◽

pp. 8322-8332 ◽

Cited By ~ 2

Author(s):

Xiaohong Lv ◽

Yun Gao ◽

Tantan Dong ◽

Libo Yang

Keyword(s):

Natural Killer ◽

Type Ii Diabetes ◽

Nkt Cells ◽

Vascular Injuries ◽

Type Ii ◽

Natural Killer T

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Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00200.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. G269-G276 ◽

Cited By ~ 17

Author(s):

Sidsel Støy ◽

Anders Dige ◽

Thomas Damgaard Sandahl ◽

Tea Lund Laursen ◽

Christian Buus ◽

...

Keyword(s):

T Lymphocytes ◽

Nk Cells ◽

Natural Killer ◽

Cytotoxic T Lymphocytes ◽

Alcoholic Hepatitis ◽

Nk Cell ◽

Alcoholic Cirrhosis ◽

Nkt Cells ◽

Receptor Expression ◽

Healthy Controls

The dynamics and role of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and NKT cells in the life-threatening inflammatory disease alcoholic hepatitis is largely unknown. These cells directly kill infected and damaged cells through, e.g., degranulation and interferon-γ (IFNγ) production, but cause tissue damage if overactivated. They also assist tissue repair via IL-22 production. We, therefore, aimed to investigate the frequency, functionality, and activation state of such cells in alcoholic hepatitis. We analyzed blood samples from 24 severe alcoholic hepatitis patients followed for 30 days after diagnosis. Ten healthy abstinent volunteers and 10 stable abstinent alcoholic cirrhosis patients were controls. Using flow cytometry we assessed cell frequencies, NK cell degranulation capacity following K562 cell stimulation, activation by natural killer group 2 D (NKG2D) expression, and IL-22 and IFNγ production. In alcoholic hepatitis we found a decreased frequency of CTLs compared with healthy controls ( P < 0.001) and a similar trend for NK cells ( P = 0.089). The NK cell degranulation capacity was reduced by 25% compared with healthy controls ( P = 0.02) and by 50% compared with cirrhosis patients ( P = 0.04). Accordingly, the NKG2D receptor expression was markedly decreased on NK cells, CTLs, and NKT cells ( P < 0.05, all). The frequencies of IL-22-producing CTLs and NK cells were doubled compared with healthy controls ( P < 0.05, all) but not different from cirrhosis patients. This exploratory study for the first time showed impaired cellular cytotoxicity and activation in alcoholic hepatitis. This is unlikely to cause hepatocyte death but may contribute toward the severe immune incompetence. The results warrant detailed and mechanistic studies.

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Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency

PLoS ONE ◽

10.1371/journal.pone.0169681 ◽

2017 ◽

Vol 12 (1) ◽

pp. e0169681 ◽

Cited By ~ 9

Author(s):

Shintaro Sagami ◽

Yoshitaka Ueno ◽

Shinji Tanaka ◽

Akira Fujita ◽

Hiroaki Niitsu ◽

...

Keyword(s):

Natural Killer ◽

Cell Loss ◽

Type I ◽

Type Ii ◽

Choline Deficiency ◽

Nkt Cell ◽

Murine Colitis ◽

Natural Killer T

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Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors

Nature Communications ◽

10.1038/s41467-019-12941-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Catarina F. Almeida ◽

Srinivasan Sundararaj ◽

Jérôme Le Nours ◽

T. Praveena ◽

Benjamin Cao ◽

...

Keyword(s):

Nkt Cells ◽

Type I ◽

Type Ii ◽

Nkt Cell ◽

Lipid Antigens ◽

Microbial Antigen ◽

Health And Disease ◽

Lipid Antigen ◽

And Function ◽

Antigen Presenting

AbstractType I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that diverse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.

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