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 The Src Family Tyrosine Kinase Fyn Regulates Natural Killer T Cell Development

1999 ◽  
Vol 190 (8) ◽  
pp. 1189-1196 ◽  
Author(s):  
Paul Gadue ◽  
Neil Morton ◽  
Paul L. Stein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Nk Cell ◽  
T Cell Development ◽  
Receptor Activation ◽  
Cell Development ◽  
T Cell Subsets ◽  
Nk T Cells ◽  
Nk T Cell

T lymphocytes express two Src tyrosine kinases, Lck and Fyn. While thymocyte and T cell subsets are largely normal in fyn−/− mice, animals lacking Lck have impaired T cell development. Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation. The lack of cytokine induction in fyn mutant mice is due to a block in natural killer (NK) T cell development. Studies using bone marrow chimeras indicate that the defect behaves in a cell-autonomous manner, and the lack of NK T cells is probably not caused by inappropriate microenvironmental cues. Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny. The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

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 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 CD1d-restricted Recognition of Synthetic Glycolipid Antigens by Human Natural Killer T Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1529-1534 ◽  
Author(s):  
Franca M. Spada ◽  
Yasuhiko Koezuka ◽  
Steven A. Porcelli
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cell Subset ◽  
Cell Receptor ◽  
Immune Recognition ◽  
Cell Clones ◽  
Nk T Cells ◽  
Circulating T Cells ◽  
Antigen Presenting

A conserved subset of mature circulating T cells in humans expresses an invariant Vα24-JαQ T cell receptor (TCR)-α chain rearrangement and several natural killer (NK) locus–encoded C-type lectins. These human T cells appear to be precise homologues of the subset of NK1.1+ TCR-α/β+ T cells, often referred to as NK T cells, which was initially identified in mice. Here we show that human NK T cell clones are strongly and specifically activated by the same synthetic glycolipid antigens as have been shown recently to stimulate murine NK T cells. Responses of human NK T cells to these synthetic glycolipids, consisting of certain α-anomeric sugars conjugated to an acylated phytosphingosine base, required presentation by antigen-presenting cells expressing the major histocompatibility complex class I–like CD1d protein. Presentation of synthetic glycolipid antigens to human NK T cells required internalization of the glycolipids by the antigen-presenting cell and normal endosomal targeting of CD1d. Recognition of these compounds by human NK T cells triggered proliferation, cytokine release, and cytotoxic activity. These results demonstrate a striking parallel in the specificity of NK T cells in humans and mice, thus providing further insight into the potential mechanisms of immune recognition by NK T cells and the immunological function of this unique T cell subset.

scholarly journals Functionally Distinct Subsets of CD1d-restricted Natural Killer T Cells Revealed by CD1d Tetramer Staining

2002 ◽  
Vol 195 (5) ◽  
pp. 625-636 ◽  
Author(s):  
Jenny E. Gumperz ◽  
Sachiko Miyake ◽  
Takashi Yamamura ◽  
Michael B. Brenner
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Cytokine Production ◽  
Interferon Γ ◽  
Tumor Rejection ◽  
Inflammatory Factors ◽  
Th2 Cytokines ◽  
Microbial Infections ◽  
Nk T Cells ◽  
Perforin Expression

CD1d-restricted natural killer (NK)T cells are known to potently secrete T helper (Th)1 and Th2 cytokines and to mediate cytolysis, but it is unclear how these contrasting functional activities are regulated. Using lipid antigen–loaded CD1d tetramers, we have distinguished two subsets of CD1d-restricted T cells in fresh peripheral blood that differ in cytokine production and cytotoxic activation. One subset, which was CD4−, selectively produced the Th1 cytokines interferon γ and tumor necrosis factor α, and expressed NKG2d, a marker associated with cytolysis of microbially infected and neoplastic cells. This subset up-regulated perforin after exposure to interleukin (IL)-2 or IL-12. In contrast, CD4+ CD1d-restricted NKT cells potently produced both Th1 and Th2 cytokines, up-regulated perforin in response to stimulation by phorbol myristate acetate and ionomycin but not IL-2 or IL-12, and could be induced to express CD95L. Further, for both CD1d-restricted NKT cell subsets, we found that antigenic stimulation induced cytokine production but not perforin expression, whereas exposure to inflammatory factors enhanced perforin expression but did not stimulate cytokine production. These results show that the various activities of CD1d-restricted T cells in tumor rejection, autoimmune disease, and microbial infections could result from activation of functionally distinct subsets, and that inflammatory and antigenic stimuli may influence different effector functions.

scholarly journals Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling

2021 ◽  
Author(s):  
Juanjuan Yuan ◽  
Ting Cai ◽  
Xiaojun Zheng ◽  
Yangzi Ren ◽  
Jingwen Qi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Metabolic Regulation ◽  
Cholesterol Metabolism ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Cell Receptor ◽  
Suppressive Effect ◽  
Effector Function

AbstractMetabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8+ T cell antitumor activity. Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion, we also found a non-canonical function of LDLR in CD8+ T cells: LDLR interacts with the T-cell receptor (TCR) complex and regulates TCR recycling and signaling, thus facilitating the effector function of cytotoxic T-lymphocytes (CTLs). Furthermore, we found that the tumor microenvironment (TME) downregulates CD8+ T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs. Moreover, genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hypercholesterolemia target, this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.

scholarly journals A role for interleukin 4 in the differentiation of mature T cell receptor gamma/delta + cells from human intrathymic T cell precursors.

1990 ◽  
Vol 172 (2) ◽  
pp. 439-446 ◽  
Author(s):  
A Bárcena ◽  
M L Toribio ◽  
L Pezzi ◽  
C Martínez
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Critical Role ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Gamma Delta ◽  
Consistent Finding ◽  
Delta Cells ◽  
Gamma Delta Cells

We have analyzed the effect of human recombinant interleukin 4 (rIL-4) on the growth and differentiation of human intrathymic pre-T cells (CD7+2+1-3-4-8-). We describe that this population of T cell precursors proliferates in response to rIL-4 (in the absence of mitogens or other stimulatory signals) in a dose-dependent way. The IL-4-induced proliferation is independent of the IL-2 pathway, as it cannot be inhibited with an anti-IL-2 receptor alpha chain antibody. In our culture conditions, rIL-4 also promotes the differentiation of pre-T cells into phenotypically mature T cells. Although both CD3/T cell receptor (TCR)-alpha/beta + and CD3-gamma/delta + T cells were obtained, the preferential differentiation into TCR-gamma/delta + cells was a consistent finding. These results suggest that, in addition to IL-2, IL-4 plays a critical role in promoting growth and differentiation of intrathymic T cell precursors at early stages of T cell development.

scholarly journals The Molecular Adapter Carma1 Controls Entry of IκB Kinase into the Central Immune Synapse

2004 ◽  
Vol 200 (9) ◽  
pp. 1167-1177 ◽  
Author(s):  
Hiromitsu Hara ◽  
Christopher Bakal ◽  
Teiji Wada ◽  
Denis Bouchard ◽  
Robert Rottapel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Lymphocyte Function ◽  
Specific System ◽  
Immune Synapse ◽  
Iκb Kinase

Carma1 (also known as caspase recruitment domain [CARD]11, Bimp3) is a CARD-containing membrane-associated guanylate kinase family protein that plays an essential role in antigen receptor–induced nuclear factor κB activation. We investigated the role of Carma1 in the assembly of signaling molecules at the immune synapse using a peptide-specific system. We report that Carma1 is essential for peptide-induced interleukin 2 and interferon γ production, but dispensable for proliferation in T cells. Recruitment and distribution of T cell receptor, lymphocyte function associated 1, lipid rafts, and protein kinase C (PKC)θ to central and peripheral immune synapse regions occur normally in Carma1−/− T cells. Carma1 controls entry of IκB kinase (IKK) into lipid raft aggregates and the central region of the immune synapse, as well as activation of IKK downstream of PKC. Our data provide the first genetic evidence on a new class of molecular scaffold that controls entry of defined signaling components, IKK, into the central supramolecular activation cluster at T cell–antigen-presenting cell interfaces without having any apparent effect on the overall organization and formation of immune synapses.

scholarly journals Follicular lymphoma tumor–infiltrating T-helper (TH) cells have the same polyfunctional potential as normal nodal TH cells despite skewed differentiation

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3591-3602 ◽  
Author(s):  
Shannon P. Hilchey ◽  
Alexander F. Rosenberg ◽  
Ollivier Hyrien ◽  
Shelley Secor-Socha ◽  
Matthew R. Cochran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Critical Role ◽  
Cell Receptor ◽  
Effector Memory ◽  
T Helper ◽  
Th Cells ◽  
Lineage Differentiation ◽  
Th Cell

Abstract The follicular lymphoma (FL) T-cell microenvironment plays a critical role in the biology of this disease. We therefore determined the lineage, differentiation state, and functional potential of FL-infiltrating CD4+ T-helper cells (TH) compared with reactive and normal lymph node (NLN) TH cells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effector memory TH cells. We further show differences in the distribution and anatomical localization of CXCR5+ TH populations that, on the basis of transcription factor analysis, include both regulatory and follicular helper T cells. On Staphylococcus enterotoxin-B stimulation, which stimulates T cells through the T-cell receptor, requires no processing by APCs, and can overcome regulator T cell-mediated suppression, the proportion of uncommitted primed precursor cells, as well as TH2 and TH17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of TH1 and polyfunctional TH cells (producing multiple cytokines simultaneously) is similar in FL cells and NLNs. These data suggest that, although TH-cell differentiation in FL is skewed compared with NLNs, FL TH cells should have the same intrinsic ability to elicit antitumor effector responses as NLN TH cells when tumor suppressive mechanisms are attenuated.

scholarly journals Programmed death-1 (PD-1) defines a transient and dysfunctional oligoclonal T cell population in acute homeostatic proliferation

2007 ◽  
Vol 204 (10) ◽  
pp. 2321-2333 ◽  
Author(s):  
Sue-Jane Lin ◽  
Craig D. Peacock ◽  
Kapil Bahl ◽  
Raymond M. Welsh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Annexin V ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Homeostatic Proliferation ◽  
Programmed Death ◽  
Cell Fractions

The host responds to lymphopenic environments by acute homeostatic proliferation, which is a cytokine- and endogenous peptide-driven expansion of lymphocytes that restores the numbers and diversity of T cells. It is unknown how these homeostatically proliferating (HP) cells are ultimately controlled. Using a system where lymphocytic choriomeningitis virus–immune C57BL/6 splenocytes were transferred into lymphopenic T cell–deficient hosts and allowed to reconstitute the environment, we defined the following three populations of T cells: slowly dividing Ly6C+ cells, which contained bona fide virus-specific memory cells, and more rapidly dividing Ly6C− cells segregating into programmed death (PD)-1+ and PD-1− fractions. The PD-1+ HP cell population, which peaked in frequency at day 21, was dysfunctional in that it failed to produce interferon γ or tumor necrosis factor α on T cell receptor (TCR) stimulation, had down-regulated expression of interleukin (IL)-7Rα, IL-15Rβ, and Bcl-2, and reacted with Annexin V, which is indicative of a preapoptotic state. The PD-1+ HP cells, in contrast to other HP cell fractions, displayed highly skewed TCR repertoires, which is indicative of oligoclonal expansion; these skewed repertoires and the PD-1+ population disappeared by day 70 from the host, presumably because of apoptosis. These results suggest that PD-1 may play a negative regulatory role to control rapidly proliferating and potentially pathogenic autoreactive CD8+ T cells during homeostatic reconstitution of lymphopenic environments.

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