scholarly journals During Trypanosoma cruzi Infection CD1d-Restricted NK T Cells Limit Parasitemia and Augment the Antibody Response to a Glycophosphoinositol-Modified Surface Protein

2002 ◽  
Vol 70 (1) ◽  
pp. 36-48 ◽  
Author(s):  
Malcolm S. Duthie ◽  
Monika Wleklinski-Lee ◽  
Sherilyn Smith ◽  
Toshinori Nakayama ◽  
Masaru Taniguchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Response ◽  
Inflammatory Responses ◽  
Chronic Phase ◽  
Surface Protein ◽  
Nk T Cells ◽  
Modified Surface ◽  
Nk T Cell ◽  
Deficient Mice

ABSTRACT Trypanosoma cruzi is a protozoan parasite that chronically infects many mammalian species and in humans causes Chagas’ disease, a chronic inflammatory disease. The parasite expresses glycophosphoinositol (GPI), which potently stimulates interleukin 12 (IL-12) production. During T. cruzi infection IL-12, and possibly GPI, might stimulate NK T cells to affect the protective and chronic inflammatory responses. Here we report that during T. cruzi infection CD1d-restricted NK T cells are stimulated as NK T-cell-deficient mice have greater parasitemia. Furthermore, during T. cruzi infection the percentages of NK T cells in the liver and spleen become decreased for prolonged periods of time, and in vitro stimulation of NK T cells derived from livers of chronically infected mice, compared to uninfected mice, results in increased gamma interferon and IL-4 secretion. Moreover, in NK T-cell-deficient mice the chronic-phase antibody response to a GPI-modified surface protein is decreased. These results indicate that, during the acute infection, NK T cells limit parasitemia and that, during the chronic phase, NK T cells augment the antibody response. Thus, during T. cruzi infection the quality of an individual’s NK T-cell response can affect the level of parasitemia and parasite tissue burden, the intensity of the chronic inflammatory responses, and possibly the outcome of Chagas’ disease.

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.

Mechanisms by Which NK T Cells Become the Predominant T Cell Subset in Mice after Irradiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4295-4295
Author(s):  
Zhenyu Yao ◽  
Yinping Liu ◽  
Jennifer McIntire ◽  
Samuel Strober
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Absolute Number ◽  
T Cell Subsets ◽  
Brdu Incorporation ◽  
T Cell Subset ◽  
Nk T Cells ◽  
The Absolute ◽  
Nk T Cell

Abstract Previously, we found that the percentage of NK T cells among all T cells in the spleen of mice treated with fractionated irradiation to the lymphoid tissues (Total lymphoid irradiation; TLI) with a total dose of 4,080 cGy increased markedly due to greater reduction in the absolute number of non-NK T cells as compared to NK T cells. The underlying mechanisms of the change in the T cell subsets after irradiation remained to be established. In the current study, C57BL/6 mice were given escalating single doses of 240, 1,000, 2,000 and 3,000 cGy total body irradiation (TBI). Splenocytes were harvested at 4 or 24 hours after irradiation, and the percentage and absolute number of NK T and non-NK T cells was determined. At the same time, the intracellular level of the anti-apoptotic protein, Bcl-2 was assayed by flow cytometry. In some studies, the turnover rate of NK T cells and non-NK T cells was examined by injection of BrdU and intracellular staining. At 4 hours after all doses of irradiation, neither the NK T nor non-NK T cell subset had a significant change in percentage or absolute number as compared to untreated controls. However, at 24 hours the percentage of NK T cells among all T cells had progressively increased with increased doses of TBI from 3% in the untreated controls to 65% in mice given 3,000 cGy. Whereas the absolute number of non-NK T cells decreased at least 1000 fold, the absolute number of NK T cells decreased approximately 50 fold after 3,000 cGy. The BrdU incorporation of NK T cells from irradiated mice was markedly reduced as compared to untreated mice, and was similar to that of non NK T cells in these irradiated mice. 8–12% of NK T cells and non NK T cells in untreated mice expressed a high level Bcl-2. As the dose of TBI increased progressively, the percentage of Bcl-2hi cells increased progressively to 89% amongst NK T cells and 70% amongst non-NK T cells. At each irradiation dose, the percentage of Bcl-2hi cells amongst NK T cells was higher than amongst non-NK T cells. There were 40×103 Bcl-2hi NK T cell and 10×103 Bcl-2hi non-NK T cells surviving per spleen at 24 hours after 3000 cGy TBI. The absolute number of Bcl-2hi NK T cells decreased by about two fold while the absolute number of Bcl-2hi non-NK T cells decreased by about 100 fold. These results indicate that the increased percentage of NK T cells amongst all T cells after irradiation is due to greater radioresistance rather than to more rapid replenishment of NK T cells as compared to non-NK T cells. We are investigating whether Bcl-2 plays a critical role in the extraordinary radioresistance of the NK T cells.

scholarly journals CD4 T-Cell-Independent Antibody Response Reduces Enterovirus 71 Lethality in Mice by Decreasing Tissue Viral Loads

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Li-Chiu Wang ◽  
Chia-Min Kao ◽  
Pin Ling ◽  
Ih-Jen Su ◽  
Tung-Miao Chang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Response ◽  
Viral Infection ◽  
Neutralizing Antibodies ◽  
Enterovirus 71 ◽  
Cd4 T Cell ◽  
Wild Type ◽  
Viral Loads ◽  
Deficient Mice

Enterovirus 71 (EV71) has induced fatal encephalitis in hundreds of thousands of infants and young children in the Asia-Pacific region since the past decade. Lymphocyte and antibody responses have been suspected to aggravate EV71-induced neurological symptoms, so anti-inflammatory agents have been used to treat patients with neurological symptoms. In the present study, we found that mice deficient in CD4+T cells were resistant to EV71 infection as wild-type mice, whereas mice deficient in B cells were highly susceptible to viral infection. Compensation of CD4 T-cell function by other immune cells was not likely, because wild-type mice depleted of CD4+T cells were also resistant to viral infection. Infected CD4 T-cell-deficient mice produced virus-specific neutralizing antibodies, IgM and IgG. Moreover, adoptive transfer of the virus-specific antibody produced by infected CD4 T-cell-deficient mice protected B-cell-deficient mice from infection by reducing tissue viral loads. Collectively, our results show that the CD4 T-cell-independent antibody response promotes the survival of EV71-infected mice and suggest great potential for the use of vaccines and neutralizing antibodies to reduce fatal symptoms in patients.

scholarly journals Generation and Characterization of B7-H4/B7S1/B7x-Deficient Mice

2006 ◽  
Vol 26 (17) ◽  
pp. 6403-6411 ◽  
Author(s):  
Woong-Kyung Suh ◽  
Seng Wang ◽  
Gordon S. Duncan ◽  
Yoshiyuki Miyazaki ◽  
Elizabeth Cates ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leishmania Major ◽  
Inflammatory Responses ◽  
Fine Tuning ◽  
Th2 Cells ◽  
The Impact ◽  
Deficient Mice

ABSTRACT Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.

CS-1 Is Expressed in Nasal Type NK/T Cell Lymphomas and Angioimmunoblastic T-Cell Lymphomas: Implications for Targeted Therapy with Elotuzumab (HuLuc63).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1779-1779
Author(s):  
Eric D Hsi ◽  
Roxanne Steinle ◽  
Balaji Balasa ◽  
Audie Rice ◽  
Young-Hyeh Ko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Expression Profiling ◽  
Nasal Type ◽  
T Cell Lymphomas ◽  
Nk T Cells ◽  
Nk T Cell ◽  
Peripheral T Cell Lymphomas

Abstract Background: CS-1 (CRACC, SLAMF7, CD319) is a member of the signaling lymphocyte activating molecule-related receptor family. It is highly and uniformly expressed on the cell surface of benign and malignant plasma cells. We have recently reported the generation of elotuzumab (formerly known as HuLuc63), a humanized antibody targeting CS-1, which is currently in phase 1 trials in relapsed multiple myeloma. Lower levels of CS-1 have also been reported on NK cells and NK-like T-cells (NK/T). CS-1 expression in NK and T-cell lymphomas - aggressive lymphomas for which no effective therapy exists - is unknown. Here, we examined the expression of CS-1 in normal NK/T cells and in a series of NK and peripheral T-cell lymphomas (PTCL). Methods: CS-1 expression in normal NK and T-cells were assessed by gene expression profiling. Flow cytometry (FACSCalibur, Becton Dickinson) was performed on blood from normal samples using a directly conjugated Alexa-488 elotuzumab. Archival formalin-fixed, paraffin-embedded tissues from PTCLs, including angioimmunoblastic T-cell lymphomas (AITL) and nasal type NK/T cell lymphomas were tested for CS-1 expression using the a paraffin-reactive 1G9 monoclonal antibody and automated immunohistochemistry (IHC, Ventana Medical Systems). Results: Gene expression profiling showed CS-1 expression in purified NK and NK/T cells. We confirmed cell surface expression of CS-1 protein on normal blood NK and NK/T cells (n=18 samples) by flow cytometry with Alexa-488-HuLuc63. The majority of normal NK and NK/T cells expressed CS-1 (mean% positive and standard deviation of 96% +/− 4% and 71 % +/− 24%, respectively). We then evaluated tumor samples from patients with nasal type NK/T cell lymphoma as well as other peripheral T-cell lymphomas by IHC. Biopsies from 13 patients (5 from the United States, 8 from Korea) with nasal type NK/T cell lymphomas were evaluated by IHC. 12 of 13 (92%) patient samples expressed CS-1 with most cases showing a majority of cells positive. 46 PTCLs were also evaluated (including 9 AITL). Overall, 8/46 (17%) of the PTCL cases expressed CS-1. However, of the AITLs, 4 of 9 (44%) expressed CS-1. Conclusions: CS-1 is expressed on nearly all nasal type NK/T cell lymphomas and in a substantial proportion of AITLs. These results provide the rationale for exploring elotuzumab in the targeted treatment of NK/T-cell malignancies.

scholarly journals The Mouse Cd1d-Restricted Repertoire Is Dominated by a Few Autoreactive T Cell Receptor Families

2001 ◽  
Vol 193 (8) ◽  
pp. 893-904 ◽  
Author(s):  
Se-Ho Park ◽  
Angela Weiss ◽  
Kamel Benlagha ◽  
Tim Kyin ◽  
Luc Teyton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Autoreactive T Cell ◽  
Tcr Repertoire ◽  
Nk T Cells ◽  
Innate Lymphocytes ◽  
Deficient Mice

To define the phenotype and T cell receptor (TCR) repertoire of CD1d-dependent T cells, we compared the populations of T cells that persisted in major histocompatibility complex (MHC)-deficient mice, which lack mainstream T cells, with those from MHC/CD1d doubly deficient mice, which lack both mainstream and CD1d-dependent T cells. Surprisingly, up to 80% of the CD1d-dependent T cells were stained by tetramers of CD1d/α-galactosylceramide, which specifically identify the previously described CD1d autoreactive Vα14-Jα18/Vβ8 natural killer (NK) T cells. Furthermore, zooming in on the CD1d-dependent non-Vα14 T cells, we found that, like Vα14 NK T cells, they mainly expressed recurrent, CD1d autoreactive TCR families and had a natural memory phenotype. Thus, CD1d-restricted T cells differ profoundly from MHC-peptide–specific T cells by their predominant use of autoreactive and semiinvariant, rather than naive and diverse, TCRs. They more closely resemble other lineages of innate lymphocytes such as B-1 B cells, γδ T cells, and NK cells, which express invariant or semiinvariant autoreactive receptors. Finally, we demonstrate that the MHC-restricted TCR repertoire is essentially non–cross-reactive to CD1d. Altogether, these findings imply that lipid recognition by CD1d-restricted T cells may have largely evolved as an innate rather than an adaptive arm of the mouse immune system.

scholarly journals Interleukin-23 Orchestrates Mucosal Responses to Salmonella enterica Serotype Typhimurium in the Intestine

2008 ◽  
Vol 77 (1) ◽  
pp. 387-398 ◽  
Author(s):  
Ivan Godinez ◽  
Manuela Raffatellu ◽  
Hiutung Chu ◽  
Tatiane A. Paixão ◽  
Takeshi Haneda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Mucosa ◽  
Salmonella Enterica ◽  
Inflammatory Responses ◽  
Γδ T Cells ◽  
Wild Type ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Cecal Mucosa

ABSTRACT Salmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the ceca of streptomycin-pretreated mice that involves T-cell-dependent induction of gamma interferon (IFN-γ), interleukin-22 (IL-22), and IL-17 expression (genes Ifn-γ, Il-22, and Il-17, respectively). We investigated here the role of IL-23 in initiating these inflammatory responses using the streptomycin-pretreated mouse model. Compared to wild-type mice, the expression of IL-17 was abrogated, IL-22 expression was markedly reduced, but IFN-γ expression was normal in the ceca of IL-23p19-deficient mice during serotype Typhimurium infection. IL-23p19-deficient mice also exhibited a markedly reduced expression of regenerating islet-derived 3 gamma, keratinocyte-derived cytokine, and reduced neutrophil recruitment into the cecal mucosa during infection. Analysis of CD3+ lymphocytes in the intestinal mucosa by flow cytometry revealed that αβ T cells were the predominant cell type expressing the IL-23 receptor in naive mice. However, a marked increase in the number of IL-23 receptor-expressing γδ T cells was observed in the lamina propria during serotype Typhimurium infection. Compared to wild-type mice, γδ T-cell-receptor-deficient mice exhibited blunted expression of IL-17 during serotype Typhimurium infection, while IFN-γ expression was normal. These data suggested that γδ T cells are a significant source, but not the sole source, of IL-17 in the acutely inflamed cecal mucosa of mice. Collectively, our results point to IL-23 as an important player in initiating a T-cell-dependent amplification of inflammatory responses in the intestinal mucosa during serotype Typhimurium infection.

scholarly journals A Subset of Liver NK T Cells Is Activated during Leishmania donovani Infection by CD1d-bound Lipophosphoglycan

2004 ◽  
Vol 200 (7) ◽  
pp. 895-904 ◽  
Author(s):  
Joseph L. Amprey ◽  
Jin S. Im ◽  
Salvatore J. Turco ◽  
Henry W. Murray ◽  
Petr A. Illarionov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leishmania Donovani ◽  
Early Response ◽  
Leishmania Infection ◽  
Wild Type ◽  
High Affinity ◽  
Nk T Cells ◽  
Nk T Cell ◽  
Increased Susceptibility

Natural killer (NK) T cells are activated by synthetic or self-glycolipids and implicated in innate host resistance to a range of viral, bacterial, and protozoan pathogens. Despite the immunogenicity of microbial lipoglycans and their promiscuous binding to CD1d, no pathogen-derived glycolipid antigen presented by this pathway has been identified to date. In the current work, we show increased susceptibility of NK T cell–deficient CD1d−/− mice to Leishmania donovani infection and Leishmania-induced CD1d-dependent activation of NK T cells in wild-type animals. The elicited response was Th1 polarized, occurred as early as 2 h after infection, and was independent from IL-12. The Leishmania surface glycoconjugate lipophosphoglycan, as well as related glycoinositol phospholipids, bound with high affinity to CD1d and induced a CD1d-dependent IFNγ response in naive intrahepatic lymphocytes. Together, these data identify Leishmania surface glycoconjugates as potential glycolipid antigens and suggest an important role for the CD1d–NK T cell immune axis in the early response to visceral Leishmania infection.

Sign in / Sign up

Export Citation Format

Share Document