scholarly journals Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers

2000 ◽  
Vol 192 (5) ◽  
pp. 741-754 ◽  
Author(s):  
Jennifer L. Matsuda ◽  
Olga V. Naidenko ◽  
Laurent Gapin ◽  
Toshinori Nakayama ◽  
Masaru Taniguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Cell Number ◽  
Interleukin 4 ◽  
Regulatory Function ◽  
Nk T Cells ◽  
Lipid Antigen

A major group of natural killer (NK) T cells express an invariant Vα14+ T cell receptor (TCR) specific for the lipoglycan α-galactosylceramide (α-GalCer), which is presented by CD1d. These cells may have an important immune regulatory function, but an understanding of their biology has been hampered by the lack of suitable reagents for tracking them in vivo. Here we show that tetramers of mouse CD1d loaded with α-GalCer are a sensitive and highly specific reagent for identifying Vα14+ NK T cells. Using these tetramers, we find that α-GalCer–specific T lymphocytes are more widely distributed than was previously appreciated, with populations of largely NK1.1− but tetramer-binding T cells present in the lymph nodes and the intestine. Injection of α-GalCer leads to the production of both interferon γ and interleukin 4 by nearly all NK T cells in the liver and the majority of the spleen within 2 h. These cells mostly disappear by 5 h, and they do not reappear after 1 wk. Curiously, tetramer-positive thymocytes do not rapidly synthesize cytokines, nor do they undergo decreases in cell number after lipid antigen stimulation, although they express equivalent TCR levels. In summary, the data presented here demonstrate that α-GalCer–specific NK T cells undergo a unique and highly compartmentalized response to antigenic stimulation.

scholarly journals A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas

2002 ◽  
Vol 196 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Nadine Y. Crowe ◽  
Mark J. Smyth ◽  
Dale I. Godfrey
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Critical Role ◽  
Physiological Role ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Tumor Rejection ◽  
Nk T Cells ◽  
Nk T Cell

Natural killer (NK) T cells initiate potent antitumor responses when stimulated by exogenous factors such as interleukin (IL)-12 or α-galactosylceramide (α-GalCer), however, it is not clear whether this reflects a physiological role for these cells in tumor immunity. Through adoptive transfer of NK T cells from wild-type to NK T cell–deficient (T cell receptor [TCR] Jα281−/−) mice, we demonstrate a critical role for NK T cells in immunosurveillance of methylcholanthrene (MCA)-induced fibrosarcomas, in the absence of exogenous stimulatory factors. Using the same approach with gene-targeted and/or antibody-depleted donor or recipient mice, we have shown that this effect depends on CD1d recognition and requires the additional involvement of both NK and CD8+ T cells. Interferon-γ production by both NK T cells and downstream, non-NK T cells, is essential for protection, and perforin production by effector cells, but not NK T cells, is also critical. The protective mechanisms in this more physiologically relevant system are distinct from those associated with α-GalCer–induced, NK T cell–mediated, tumor rejection. This study demonstrates that, in addition to their importance in tumor immunotherapy induced by IL-12 or α-GalCer, NK T cells can play a critical role in tumor immunosurveillance, at least against MCA-induced sarcomas, in the absence of exogenous stimulation.

scholarly journals CD1d-restricted Human Natural Killer T Cells Are Highly Susceptible to Human Immunodeficiency Virus 1 Infection

2002 ◽  
Vol 195 (7) ◽  
pp. 869-879 ◽  
Author(s):  
Alison Motsinger ◽  
David W. Haas ◽  
Aleksandar K. Stanic ◽  
Luc Van Kaer ◽  
Sebastian Joyce ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Natural Killer ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Immunodeficiency Virus ◽  
Nk T Cells ◽  
Killer T Cells ◽  
Hiv 1

Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Vα24-Vβ11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Vα24+ T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with α-galactosylceramide (α-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4+ T cells. Furthermore, resting CD4+ NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4+ subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4+ NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.

scholarly journals Identification and characterization of IL-10/IFN-γ–producing effector-like T cells with regulatory function in human blood

2009 ◽  
Vol 206 (5) ◽  
pp. 1009-1017 ◽  
Author(s):  
Barbara Häringer ◽  
Laura Lozza ◽  
Bodo Steckel ◽  
Jens Geginat
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Blood ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Regulatory Function ◽  
Ki 67 ◽  
Effector Cells

Two subsets of natural and adaptive regulatory T (T reg) cells have been described, but the identity of adaptive type 1 regulatory (Tr1)–like cells in humans is unclear. We analyzed a subset of human blood CD4+ T cells—CD45RA−CD25−interleukin (IL)-7 receptor (R)− cells—that rapidly secreted high levels of IL-10 together with interferon γ, but produced little IL-2. These IL-7R− T cells were rare, anergic, and largely Foxp3−. They expressed low levels of Bcl-2 but high levels of Ki-67 and ICOS, suggesting that they have been recently activated in vivo. Consistently, they responded selectively to persistent foreign and self-antigens under steady-state conditions. Unlike natural CD25+ T reg cells, IL-7R− cells suppressed naive and memory T cell proliferation in an IL-10–dependent fashion, and they required strong T cell receptor stimulation for suppression. To our knowledge, this is the first report that identifies Tr1-like cells in human blood. These IL-10–secreting cells have characteristics of chronically activated Th1 effector cells and are distinct from CD25+ T reg cells.

Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2415-2420 ◽  
Author(s):  
Pierre Gourdy ◽  
Luiza M. Araujo ◽  
Ren Zhu ◽  
Barbara Garmy-Susini ◽  
Séverine Diem ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Interleukin 4 ◽  
Response To Treatment ◽  
Inkt Cells ◽  
Gender Dimorphism ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Mechanisms accounting for gender dimorphism during immune responses are still poorly understood. Since invariant natural killer T (iNKT) cells exert important regulatory functions through their capacity to produce both T helper 1 (Th1) and Th2 cytokines, we addressed the question of whether these activities could be modulated by sexual hormones. We found that in vivo challenge with the specific ligand of iNKT cells, α-galactosylceramide (α-GalCer), induced significantly higher concentrations of interferon γ (IFN-γ) in the serum of female than in that of male mice, while interleukin 4 (IL-4) production was not modified. In support of a crucial role of ovarian hormones in this phenomenon, a significant decrease of serum IFN-γ concentrations occurred in ovariectomized females, in response to treatment with α-GalCer, while orchidectomy affected neither IFN-γ nor IL-4 serum concentrations in males. The implication of estrogens in this selective enhancement of IFN-γ production by iNKT cells was demonstrated by (1) the increased α-GalCer–induced IFN-γ synthesis by iNKT cells upon both in vitro and in vivo exposure to estradiol and (2) the abolition of the sex-linked difference in α-GalCer–induced IFN-γ release in estrogen receptor α-deficient mice. These results provide the first evidence that estrogens influence iNKT cells leading to this gender dimorphism in their cytokine production profile.

scholarly journals The Leishmania major LACK Antigen with an Immunodominant Epitope at Amino Acids 156 to 173 Is Not Required for Early Th2 Development in BALB/c Mice

2004 ◽  
Vol 72 (12) ◽  
pp. 6924-6931 ◽  
Author(s):  
Ben L. Kelly ◽  
Richard M. Locksley
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Leishmania Major ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Wild Type ◽  
Immunodominant Epitope ◽  
Fusion Construct ◽  
Th2 Immune Response

ABSTRACT The Leishmania major LACK antigen contains an immunodominant epitope at amino acids 156 to 173 (LACK156-173) that is believed to nucleate the pathological Th2 immune response in susceptible BALB/c mice. To test this hypothesis, we generated L. major parasites that express a mutated LACK that fails to activate Vβ4/Vα8 T-cell receptor transgenic T cells specific for this epitope. Although mutant parasites attenuated the expansion of endogenous LACK-specific, interleukin-4 (IL-4)-expressing, CD4 T cells compared to wild-type parasites in vivo, the overall frequency of IL-4 and gamma interferon-secreting lymphocytes was similar to that elicited by wild-type L. major. Mutant parasites demonstrated diminished amastigote viability and delayed lesion development in mice, although parasites could be recovered over 200 days after infection. Complementation with a wild-type lack fusion construct partially rescued these defects, indicating a role for endogenous LACK in parasitism. Mice inoculated with mutant parasites were not protected against subsequent infection with wild-type L. major.

Differential production of interferon-γ and interleukin-4 in response to Th1- and Th2-stimulating pathogens by γδ T cells in vivo

Nature ◽  
1995 ◽  
Vol 373 (6511) ◽  
pp. 255-257 ◽  
Author(s):  
David A. Ferrick ◽  
Mark D. Schrenzel ◽  
Thera Mulvania ◽  
Beryl Hsieh ◽  
Walter G. Ferlin ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th1 And Th2

scholarly journals The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D–target-cell interactions

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3666-3672 ◽  
Author(s):  
Giuseppe Sconocchia ◽  
Michelle Lau ◽  
Maurizio Provenzano ◽  
Katayoun Rezvani ◽  
Wachanan Wongsena ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Chronic Myelogenous Leukemia ◽  
Immune Escape ◽  
Nk Cell ◽  
Myelogenous Leukemia ◽  
Cd34 Cells ◽  
Nk T Cells ◽  
Macrophage Colony

AbstractTo study natural killer (NK) cell–mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56+ cells to inhibit granulocyte macrophage–colony-forming unit (CFU-GM) formation by leukemic CD34+ cells. In 14 HLA-identical donor-recipient pairs, donor CD56+ cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% ± 9% vs 39.5% ± 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56+CD3- (natural killer [NK]) and CD56+CD3+(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34+ cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain–related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, in vivo, CML cells may avoid NK-cell–mediated immune destruction by immune escape, shedding MICA into the plasma, thereby down-regulating NKG2D on CML CD56+ cells.

scholarly journals CD1d-mediated Recognition of an α-Galactosylceramide by Natural Killer T Cells Is Highly Conserved through Mammalian Evolution

1998 ◽  
Vol 188 (8) ◽  
pp. 1521-1528 ◽  
Author(s):  
Laurent Brossay ◽  
Mariacristina Chioda ◽  
Nicolas Burdin ◽  
Yasuhiko Koezuka ◽  
Giulia Casorati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Human Peripheral Blood ◽  
Cell Subset ◽  
Cell Receptor ◽  
Recognition System ◽  
Human T Cells ◽  
Nk T Cells ◽  
Killer T Cells

Natural killer (NK) T cells are a lymphocyte subset with a distinct surface phenotype, an invariant T cell receptor (TCR), and reactivity to CD1. Here we show that mouse NK T cells can recognize human CD1d as well as mouse CD1, and human NK T cells also recognize both CD1 homologues. The unprecedented degree of conservation of this T cell recognition system suggests that it is fundamentally important. Mouse or human CD1 molecules can present the glycolipid α-galactosylceramide (α-GalCer) to NK T cells from either species. Human T cells, preselected for invariant Vα24 TCR expression, uniformly recognize α-GalCer presented by either human CD1d or mouse CD1. In addition, culture of human peripheral blood cells with α-GalCer led to the dramatic expansion of NK T cells with an invariant (Vα24+) TCR and the release of large amounts of cytokines. Because invariant Vα14+ and Vα24+ NK T cells have been implicated both in the control of autoimmune disease and the response to tumors, our data suggest that α-GalCer could be a useful agent for modulating human immune responses by activation of the highly conserved NK T cell subset.

scholarly journals Interferon gamma production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking.

1996 ◽  
Vol 183 (5) ◽  
pp. 2391-2396 ◽  
Author(s):  
H Arase ◽  
N Arase ◽  
T Saito
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Nk Cell ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Cross Linking ◽  
Target Cells ◽  
Ifn Gamma

Natural killer (NK) cells play an important role in immune response by producing interferon gamma (IFN-gamma) as well as exhibiting cytotoxic function. IFN-gamma produced by NK cells has been suggested to be involved in differentiation of T helper cells. On the other hand, the NKR-P1 molecule was recently identified as one of the important NK cell receptors, and it recognizes certain kinds of oligosaccharides on target cells and triggers NK cells for cytotoxicity. In the present study, we found that NK cells produce great amounts of IFN-gamma upon cross-linking of the NKR-P1 molecule. In contrast, stimulation of NK cells with IL-2 induced proliferation without producing IFN-gamma. Similar to NK cells, NK1.1+ T cells also produced IFN-gamma upon NKR-P1 cross-linking. NK1.1+ T cells produced IFN-gamma but not interleukin 4 (IL-4) upon NKR-P1 cross-linking, whereas they secreted both IFN-gamma and IL-4 upon T cell receptor cross-linking. These results indicate that NKR-P1 is a receptor molecule on NK and NK1.1+ T cells that induces not only cytotoxicity but also IFN-gamma production. Our findings provide a new pathway for IFN-gamma production by NK and NK1.1+ T cells through NKR-P1 molecules; it may be essential for immune regulation.

scholarly journals Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice

2000 ◽  
Vol 191 (5) ◽  
pp. 771-780 ◽  
Author(s):  
Mary K. Kennedy ◽  
Moira Glaccum ◽  
Sandra N. Brown ◽  
Eric A. Butz ◽  
Joanne L. Viney ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Defense Responses ◽  
Intraepithelial Lymphocytes ◽  
Functional Maturation ◽  
Nk T Cells ◽  
Specific Pathogen ◽  
Interleukin 15

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

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