Participatory role of natural killer and natural killer T cells in atherosclerosis: lessons learned from in vivo mouse studiesThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 67-75 ◽  
Author(s):  
Stewart C. Whitman ◽  
Tanya A. Ramsamy
Keyword(s):  
Natural Killer ◽  
Complex Disease ◽  
Immune Cell ◽  
Disease Process ◽  
Density Lipoprotein ◽  
Nkt Cells ◽  
Lessons Learned ◽  
Natural Killer T

Atherosclerosis is a multifactor, highly complex disease with numerous aetiologies that work synergistically to promote lesion development. One of the emerging components that drive the development of both early- and late-stage atherosclerotic lesions is the participation of both the innate and acquired immune systems. In both humans and animal models of atherosclerosis, the most prominent cells that infiltrate evolving lesions are macrophages and T lymphocytes. The functional loss of either of these cell types reduces the extent of atherosclerosis in mice that were rendered susceptible to the disease by deficiency of either apolipoprotein E or the LDL (low density lipoprotein) receptor. In addition to these major immune cell participants, a number of less prominent leukocyte populations that can modulate the atherogenic process are also involved. This review will focus on the participatory role of two “less prominent” immune components, namely natural killer (NK) cells and natural killer T (NKT) cells. Although this review will highlight the fact that both NK and NKT cells are not sufficient for causing the disease, the roles played by both these cells types are becoming increasingly important in understanding the complexity of this disease process.

scholarly journals Mechanisms imposing the Vβ bias of Vα14 natural killer T cells and consequences for microbial glycolipid recognition

2006 ◽  
Vol 203 (5) ◽  
pp. 1197-1207 ◽  
Author(s):  
Datsen G. Wei ◽  
Shane A. Curran ◽  
Paul B. Savage ◽  
Luc Teyton ◽  
Albert Bendelac
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Optimal Solution ◽  
Nkt Cells ◽  
Cell Repertoire ◽  
Transgenic Cells ◽  
Α Chain ◽  
Natural Killer T

Mouse and human natural killer T (NKT) cells recognize a restricted set of glycosphingolipids presented by CD1d molecules, including self iGb3 and microbial α-glycuronosylceramides. The importance of the canonical Vα14-Jα18 TCR α chain for antigen recognition by NKT cells is well recognized, but the mechanisms underlying the Vβ8, Vβ7, and Vβ2 bias in mouse have not been explored. To study the influences of thymic selection and the constraints of pairing with Vα14-Jα18, we have created a population of mature T cells expressing Vα14-Jα18 TCR α chain in CD1d-deficient mice and studied its recognition properties in vitro and in vivo. Transgenic cells expressed a diverse Vβ repertoire but their recognition of endogenous ligands and synthetic iGb3 was restricted to the same biased Vβ repertoire as expressed in natural NKT cells. In contrast, α-GalCer, a synthetic homologue of microbial α-glycuronosylceramides, was recognized by a broader set of Vβ chains, including the biased NKT set but also Vβ6, Vβ9, Vβ10, and Vβ14. These surprising findings demonstrate that, whereas Vβ8, Vβ7, and Vβ2 represent the optimal solution for recognition of endogenous ligand, many Vβ chains that are potentially useful for the recognition of foreign lipids fail to be selected in the NKT cell repertoire.

scholarly journals Cd1-Reactive Natural Killer T Cells Are Required for Development of Systemic Tolerance through an Immune-Privileged Site

1999 ◽  
Vol 190 (9) ◽  
pp. 1215-1226 ◽  
Author(s):  
Koh-Hei Sonoda ◽  
Mark Exley ◽  
Scott Snapper ◽  
Steven P. Balk ◽  
Joan Stein-Streilein
Keyword(s):  
Natural Killer ◽  
Critical Role ◽  
Nkt Cells ◽  
Delayed Type Hypersensitivity ◽  
Mouse Strains ◽  
Antibody Treatment ◽  
Privileged Site ◽  
Development Of Tolerance ◽  
Natural Killer T

Systemic tolerance can be elicited by introducing antigen into an immune-privileged site, such as the eye, or directly into the blood. Both routes of immunization result in a selective deficiency of systemic delayed type hypersensitivity. Although the experimental animal model of anterior chamber–associated immune deviation (ACAID) occurs in most mouse strains, ACAID cannot be induced in several mutant mouse strains that are coincidentally deficient in natural killer T (NKT) cells. Therefore, this model for immune-privileged site–mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance. The following data show that CD1-reactive NKT cells are required for the development of systemic tolerance induced via the eye as follows: (a) CD1 knockout mice were unable to develop ACAID unless they were reconstituted with NKT cells together with CD1+ antigen-presenting cells; (b) specific antibody depletion of NKT cells in vivo abrogated the development of ACAID; and (c) anti-CD1 monoclonal antibody treatment of wild-type mice prevented ACAID development. Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes. A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.

scholarly journals The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells

1999 ◽  
Vol 189 (7) ◽  
pp. 1121-1128 ◽  
Author(s):  
Hidemitsu Kitamura ◽  
Kenji Iwakabe ◽  
Takashi Yahata ◽  
Shin-ichiro Nishimura ◽  
Akio Ohta ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Natural Killer ◽  
Cd40 Ligand ◽  
Nkt Cells ◽  
Receptor Expression ◽  
Antitumor Activities ◽  
Nkt Cell ◽  
Ifn Γ ◽  
Natural Killer T

The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.

scholarly journals Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 618-621 ◽  
Author(s):  
David H. Chang ◽  
Nancy Liu ◽  
Virginia Klimek ◽  
Hani Hassoun ◽  
Amitabha Mazumder ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Function ◽  
Nkt Cells ◽  
Interferon Γ ◽  
Therapeutic Implications ◽  
Healthy Donors ◽  
Specific Expansion ◽  
Innate Lymphocytes ◽  
Natural Killer T

Natural killer T (NKT) cells are CD1d-restricted glycolipid reactive innate lymphocytes that play an important role in protection from pathogens and tumors. Pharmacologic approaches to enhance NKT cell function will facilitate specific NKT targeting in the clinic. Here we show that lenalidomide (LEN), a novel thalidomide (Thal) analog, enhances antigen-specific expansion of NKT cells in response to the NKT ligand α-galactosylceramide (α-GalCer) in both healthy donors and patients with myeloma. NKT cells activated in the presence of LEN have greater ability to secrete interferon-γ. Antigen-dependent activation of NKT cells was greater in the presence of dexamethasone (DEX) plus LEN than with DEX alone. Therapy with LEN/Thal also led to an increase in NKT cells in vivo in patients with myeloma and del5q myelodysplastic syndrome. Together these data demonstrate that LEN and its analogues enhance CD1d-mediated presentation of glycolipid antigens and support combining these agents with NKT targeted approaches for protection against tumors.

scholarly journals Natural Killer T Cells in Various Mouse Models of Hepatitis

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Jun Guan ◽  
Gang Wang ◽  
Qin Yang ◽  
Chao Chen ◽  
Jingwen Deng ◽  
...  
Keyword(s):  
Natural Killer ◽  
Mouse Models ◽  
Fas Ligand ◽  
Basic Research ◽  
Neutrophil Infiltration ◽  
Nkt Cells ◽  
Liver Injuries ◽  
Integral Role ◽  
Natural Killer T

Natural killer T (NKT) cells are a key component of innate immunity. Importantly, a growing body of evidence indicates that NKT cells play an integral role in various acute and chronic liver injuries. NKT cells participate in the progression of an injury through the secretion of cytokines, which promote neutrophil infiltration and enhance Fas ligand (FasL) and granzyme-mediated NKT cytotoxic activity. Therefore, examining the role of NKT cells in hepatic disease is critical for a comprehensive understanding of disease pathogenesis and may provide insight into novel approaches for treatment. For more than a century, mouse models that imitate the physiopathological conditions of human disease have served as a critical tool in biological and medical basic research, including studies of liver disease. Here, we review the role of NKT cells in various mouse models of hepatitis.

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

2018 ◽  
Vol 24 ◽  
pp. 8322-8332 ◽  
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

scholarly journals A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma

2003 ◽  
Vol 197 (12) ◽  
pp. 1667-1676 ◽  
Author(s):  
Madhav V. Dhodapkar ◽  
Matthew D. Geller ◽  
David H. Chang ◽  
Kanako Shimizu ◽  
Shin-Ichiro Fujii ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer ◽  
Cell Function ◽  
Nkt Cells ◽  
Myeloma Cells ◽  
Tumor Bed ◽  
Reversible Defect ◽  
Natural Killer T

We studied the function of antitumor T and natural killer T (NKT) cells from the blood and tumor bed in 23 patients with premalignant gammopathy, nonprogressive myeloma, or progressive multiple myeloma. We show that antitumor killer T cells can be detected in patients with both progressive or nonprogressive myeloma. Vα24+Vβ11+ invariant NKT cells are detectable in the blood and tumor bed of all cohorts. However, freshly isolated NKT cells from both the blood and tumor bed of patients with progressive disease, but not nonprogressive myeloma or premalignant gammopathy, have a marked deficiency of ligand-dependent interferon-γ production. This functional defect can be overcome in vitro using dendritic cells pulsed with the NKT ligand, α-galactosylceramide (α-GalCer). Fresh myeloma cells express CD1d, and can be efficiently killed by autologous NKT cells. We hypothesize that presentation of tumor derived glycolipids by myeloma cells leads to NKT dysfunction in vivo. These data demonstrate that clinical progression in patients with monoclonal gammopathies is associated with an acquired but potentially reversible defect in NKT cell function and support the possibility that these innate lymphocytes play a role in controlling the malignant growth of this incurable B cell tumor in patients.

scholarly journals A Natural Killer T (NKT) Cell Developmental Pathway Involving a Thymus-dependent NK1.1−CD4+ CD1d-dependent Precursor Stage

2002 ◽  
Vol 195 (7) ◽  
pp. 835-844 ◽  
Author(s):  
Daniel G. Pellicci ◽  
Kirsten J.L. Hammond ◽  
Adam P. Uldrich ◽  
Alan G. Baxter ◽  
Mark J. Smyth ◽  
...  
Keyword(s):  
Natural Killer ◽  
Nkt Cells ◽  
Developmental Pathway ◽  
Nkt Cell ◽  
Tetramer Binding ◽  
Development In Vitro ◽  
A Minor ◽  
Natural Killer T

The development of CD1d-dependent natural killer T (NKT) cells is poorly understood. We have used both CD1d/α-galactosylceramide (CD1d/αGC) tetramers and anti-NK1.1 to investigate NKT cell development in vitro and in vivo. Confirming the thymus-dependence of these cells, we show that CD1d/αGC tetramer-binding NKT cells, including NK1.1+ and NK1.1− subsets, develop in fetal thymus organ culture (FTOC) and are completely absent in nude mice. Ontogenically, CD1d/αGC tetramer-binding NKT cells first appear in the thymus, at day 5 after birth, as CD4+CD8−NK1.1−cells. NK1.1+ NKT cells, including CD4+ and CD4−CD8− subsets, appeared at days 7–8 but remained a minor subset until at least 3 wk of age. Using intrathymic transfer experiments, CD4+NK1.1− NKT cells gave rise to NK1.1+ NKT cells (including CD4+ and CD4− subsets), but not vice-versa. This maturation step was not required for NKT cells to migrate to other tissues, as NK1.1− NKT cells were detected in liver and spleen as early as day 8 after birth, and the majority of NKT cells among recent thymic emigrants (RTE) were NK1.1−. Further elucidation of this NKT cell developmental pathway should prove to be invaluable for studying the mechanisms that regulate the development of these cells.

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