InVivoMAb anti-human NKG2D (CD314)
Product Details
The 1D11 monoclonal antibody reacts with human NKG2D, a type II transmembrane lectin-like glycoprotein also known as CD314. NKG2D is expressed on NK cells, NKT cells, CD8 T cells, Ī³/Ī“ T cells, and macrophages. NKG2D has been implicated in anti-tumor surveillance, the immune response against viral infection, and in diabetes progression in NOD mice. Previous studies have shown that 1D11 can block the binding of NKG2D to its ligands or stimulate the function of NKG2D-positive cells.Specifications
| Isotype | Mouse IgG1, Īŗ |
|---|---|
| Recommended Isotype Control(s) | InVivoMAb mouse IgG1 isotype control, unknown specificity |
| Recommended Dilution Buffer | InVivoPure pH 7.0 Dilution Buffer |
| Conjugation | This product is unconjugated. Conjugation is available via our Antibody Conjugation Services. |
| Immunogen | Human NKL cells |
| Reported Applications |
in vitro NKG2D blocking Immunoprecipitation Flow cytometry |
| Formulation |
PBS, pH 7.0 Contains no stabilizers or preservatives |
| Endotoxin |
<2EU/mg (<0.002EU/Ī¼g) Determined by LAL gel clotting assay |
| Purity |
>95% Determined by SDS-PAGE |
| Sterility | 0.2 Ī¼M filtered |
| Production | Purified from cell culture supernatant in an animal-free facility |
| Purification | Protein G |
| RRID | AB_2894770 |
| Molecular Weight | 150 kDa |
| Storage | The antibody solution should be stored at the stock concentration at 4Ā°C. Do not freeze. |
Recommended Products
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Recommended Isotype Control(s)
InVivoMAb mouse IgG1 isotype control, unknown specificity
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Recommended Dilution Buffer
InVivoPure pH 7.0 Dilution Buffer
in vitro NKG2D blocking
Pereira, B. I., et al. (2020). "Sestrins induce natural killer function in senescent-like CD8(+) T cells" Nat Immunol 21(6): 684-694. PubMed
Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8(+) T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27(-)CD28(-)CD8(+) T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27(-)CD28(-)CD8(+) T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27(-)CD28(-)CD8(+) T cells to acquire a broad-spectrum, innate-like killing activity.
in vitro NKG2D blocking
Parsons, M. S., et al. (2016). "NKG2D Acts as a Co-Receptor for Natural Killer Cell-Mediated Anti-HIV-1 Antibody-Dependent Cellular Cytotoxicity" AIDS Res Hum Retroviruses 32(10-11): 1089-1096. PubMed
The utility of antibody-dependent cellular cytotoxicity (ADCC) for eliminating HIV-1-infected cells is of much interest for the design of both prophylactic vaccines for HIV-1 prevention and therapeutics to eliminate latently infected cells following reactivation. Significant research has been conducted to understand the antibody specificities involved in anti-HIV-1 ADCC responses. Perhaps equally important as the identity of the antibodies mediating these responses are factors regulating the ability of ADCC effector cells, in particular, natural killer (NK) cells, to respond to antibody-coated target cells. Indeed, a plethora of activating and inhibitory receptors expressed on the surface of NK cells might act in conjunction with CD16 to influence ADCC. As the expression of NKG2D and its ligands has been linked to HIV-1 disease progression, we evaluated if signals through NKG2D were involved in anti-HIV-1 ADCC. Utilizing assays measuring cytolysis, we provide the first data implicating NKG2D in antibody-dependent NK cell responses against a target cell line either pulsed with gp120 or infected with HIV-1. These observations are highly significant for understanding antibody-dependent NK cell responses against HIV-1 and might be useful for optimizing prophylactics and therapeutics aiming to utilize antibodies and optimally functional NK cells to control HIV-1.
in vitro NKG2D blocking
Zheng, J., et al. (2015). "The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice" PLoS One 10(8): e0135999. PubMed
A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vdelta2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-gamma secreted from human Vdelta2-T cells. Meanwhile, human Vdelta2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.
in vitro NKG2D blocking
Groh, V., et al. (2001). "Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells" Nat Immunol 2(3): 255-260. PubMed
NKG2D is an activating receptor that stimulates innate immune responses by natural killer cells upon engagement by MIC ligands, which are induced by cellular stress. Because NKG2D is also present on most CD8alphabeta T cells, it may modulate antigen-specific T cell responses, depending on whether MIC moleculesādistant homologs of major histocompatibility complex (MHC) class I with no function in antigen presentationāare induced on the surface of pathogen-infected cells. We found that infection by cytomegalovirus (CMV) resulted in substantial increases in MIC on cultured fibroblast and endothelial cells and was associated with induced MIC expression in interstitial pneumonia. MIC engagement of NKG2D potently augmented T cell antigen receptor (TCR)-dependent cytolytic and cytokine responses by CMV-specific CD28- CD8alphabeta T cells. This function overcame viral interference with MHC class I antigen presentation. Combined triggering of TCR-CD3 complexes and NKG2D induced interleukin 2 production and T cell proliferation. Thus NKG2D functioned as a costimulatory receptor that can substitute for CD28.
in vitro NKG2D blocking, Immunoprecipitation, Flow Cytometry
Bauer, S., et al. (1999). "Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA" Science 285(5428): 727-729. PubMed
Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
- Cancer Research,
- Immunology and Microbiology
CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.
In Nature Cancer on 1 September 2023 by Lerner, E. C., Woroniecka, K. I., et al.
PubMed
The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D-NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants. Ā© 2023. The Author(s).
- Cancer Research,
- Immunology and Microbiology
A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8+T Cells
Preprint on BioRxiv : the Preprint Server for Biology on 3 February 2023 by Lerner, E., Woroniecka, K., et al.
PubMed
The accepted paradigm for both cellular and antitumor immunity relies upon tumor cell kill by CD8 + T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex class I (MHC I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8 + T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent on interactions between T cell NKG2D and tumor NKG2D ligands (NKG2DL). Necessarily, tumor cell kill in these instances is antigen-independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumors cells. These mechanisms are active in vivo in mice, as well as in vitro in human tumor systems, and are obviated by NKG2D knockout or blockade. Tumor cell killing following T cell NKG2D engagement is Fas-independent and appears to involve granzyme. These studies potentially obviate the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape, and instead identify the NKG2D/NKG2DL axis as a novel therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC loss variants.
- In Vitro,
- Homo sapiens (Human)
NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.
In JCI Insight on 22 December 2022 by Calabrese, D. R., Tsao, T., et al.
PubMed
Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-Ī± and IFN-Ī³ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-Ī± and IFN-Ī³ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.
- Block,
- Homo sapiens (Human),
- Immunology and Microbiology
Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands.
In Nature Communications on 15 August 2022 by Zhong, J., Yang, X., et al.
PubMed
Glioblastoma (GBM) is a highly aggressive primary brain tumour and is resistant to nearly all available treatments, including natural killer (NK) cell immunotherapy. However, the factors mediating NK cell evasion in GBM remain largely unclear. Here, we report that EZH2-92aa, a protein encoded by circular EZH2, is overexpressed in GBM and induces the immune evasion of GBM stem cells (GSCs) from NK cells. Positively regulated by DEAD-box helicase 3Ā (DDX3), EZH2-92aa directly binds the major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) promoters and represses their transcription; it also indirectly represses UL16-binding protein (ULBP) transcription by stabilizing EZH2. The downregulation of NK group 2D ligands (NKG2DLs, including MICA/B and ULBPs) in GSCs mediates NK cell resistance. Moreover, stable EZH2-92aa knockdown enhances NK cell-mediated GSC eradication in vitro and in vivo and synergizes with anti-PD1 therapy. Our results highlight the immunosuppressive function of EZH2-92aa in inhibiting the NK cell response in GBM and the clinical potential of targeting EZH2-92aa for NK-cell-directed immune therapy. Ā© 2022. The Author(s).
- Neutralization,
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
Neutralization of TGFĪ² Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma.
In Molecular Cancer Therapeutics on 1 March 2021 by Roane, B. M., Meza-Perez, S., et al.
PubMed
The immunosuppressive effects of TGFĪ² promotes tumor progression and diminishes response to therapy. In this study, we used ID8-p53-/- tumors as a murine model of high-grade serous ovarian cancer. An mAb targeting all three TGFĪ² ligands was used to neutralize TGFĪ². Ascites and omentum were collected and changes in T-cell response were measured using flow. Treatment with anti-TGFĪ² therapy every other day following injection of tumor cells resulted in decreased ascites volume (4.1 mL vs. 0.7 mL; P 0.001) and improved the CD8:Treg ratio (0.37 vs. 2.5; P = 0.02) compared with untreated mice. A single dose of therapy prior to tumor challenge resulted in a similar reduction of ascites volume (2.7 vs. 0.67 mL; P = 0.002) and increased CD8:Tregs ratio (0.36 vs. 1.49; P = 0.007), while also significantly reducing omental weight (114.9 mg vs. 93.4 mg; P = 0.017). Beginning treatment before inoculation with tumor cells and continuing for 6 weeks, we observe similar changes and prolonged overall survival (median 70 days vs. 57.5 days). TGFĪ² neutralization results in favorable changes to the T-cell response within the tumor microenvironment, leading to decreased tumor progression in ovarian cancer. The utilization of anti-TGFĪ² therapy may be an option for management in patients with ovarian cancer to improve clinical outcomes and warrants further investigation. Ā©2020 American Association for Cancer Research.
- In Vivo,
- Mus musculus (House mouse),
- Cancer Research
The Outcome of TGFĪ² Antagonism in Metastatic Breast Cancer Models In Vivo Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFĪ².
In Clinical Cancer Research on 1 February 2020 by Yang, Y., Yang, H. H., et al.
PubMed
TGFĪ²s are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFĪ² pathway are in early-phase oncology trials. However, TGFĪ²s also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored. A panel of 12 immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGFĪ² antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms. Heterogeneous responses to anti-TGFĪ² treatment were observed, with 5 of 12 models (42%) showing suppression of metastasis, 4 of 12 (33%) showing no response, and 3 of 12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, whereas stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus, the integrated outcome of TGFĪ² antagonism depends on a complex balance between enhancing effective antitumor immunity and disrupting persistent tumor-suppressive effects of TGFĪ² on the tumor cell. Applying transcriptomic signatures derived from treatment-naĆÆve mouse primary tumors to human breast cancer datasets suggested that patients with breast cancer with high-grade, estrogen receptor-negative disease are most likely to benefit from anti-TGFĪ² therapy. Contrary to dogma, tumor-suppressive responses to TGFĪ² are retained in some advanced metastatic tumors. Safe deployment of TGFĪ² antagonists in the clinic will require good predictive biomarkers. Ā©2019 American Association for Cancer Research.
- In Vivo,
- Mus musculus (House mouse)
VAMP8-mediated MUC2 mucin exocytosis from colonic goblet cells maintains innate intestinal homeostasis.
In Nature Communications on 20 September 2019 by Cornick, S., Kumar, M., et al.
PubMed
The mucus layer is the first line of innate host defense in the gut that protects the epithelium by spatially separating commensal bacteria. MUC2 mucin is produced and stored by goblet cells that is constitutively exocytosed or hyper secreted upon sensing a threat. How coordinated mucus exocytosis maintains homeostasis in the intestinal epithelium and modulates the immunological landscape remains elusive. Here we describe how the vesicle SNARE protein VAMP8 coordinates mucin exocytosis from goblet cells. Vamp8-/- exhibit a mild pro-inflammatory state basally due to an altered mucus layer and increased encounters with microbial antigens. Microbial diversity shifts to a detrimental microbiota with an increase abundance of pathogenic and mucolytic bacteria. To alleviate the heavy microbial burden and inflammatory state basally, Vamp8-/- skews towards tolerance. Despite this, Vamp8-/- is highly susceptible to both chemical and infectious colitis demonstrating the fragility of the intestinal mucosa without proper mucus exocytosis mechanisms.
- Immunology and Microbiology
Th17 cells are not required for maintenance of IL-17A-producing Ī³Ī“ T cells in vivo.
In Immunology and Cell Biology on 1 March 2017 by Gupta, P. K., Wagner, S. R., et al.
PubMed
Ī³Ī“ T cells producing interleukin-17A (Ī³Ī“T17) are thought to develop spontaneously in the thymus and to be maintained in the periphery. Previous studies suggested a role for T-helper 17 (Th17) cells in the maintenance of Ī³Ī“T17 via the expression of transforming growth factor-Ī²1 (TGFĪ²1). However, we have previously found that Th17 cells were not required for expansion of Ī³Ī“T17 cells after lung transplant in a mouse model. Using mice deficient in signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells, which are unable to develop Th17 cells, we investigated the requirement for Th17 cells and TGFĪ²1 to maintain Ī³Ī“T17 cells in the lung and lymphoid tissues. At steady state, we found no defect in Ī³Ī“T17 cells in the thymus or periphery of these mice. Further, STAT3-deficient CD4+ T cells produced significantly higher levels of TGFĪ²1 than wild-type CD4+ T cells under Th17 differentiation conditions in vitro. To determine whether STAT3-deficient CD4+ T cells could expand Ī³Ī“T17 cells in vivo, we used TCRĪ²-/- mice, which are known to have a defect in Ī³Ī“T17 cells that can be rescued by Th17 cells. However, adoptive transfer of wild-type Th17 cells or bulk CD4+ T cells did not expand Ī³Ī“T17 cells in TCRĪ²-/- mice. In contrast, interferon-Ī³+ Ī³Ī“ T cells preferentially expanded, particularly in the lungs. Interestingly, we found in vivo and in vitro that TGFĪ²1 may negatively regulate the pool of Ī³Ī“T17 cells. Our data suggest that Th17 cells and TGFĪ²1 are not required for the maintenance of Ī³Ī“T17 cells.
- Cancer Research
A novel highly potent trivalent TGF-Ī² receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands.
In Oncotarget on 27 December 2016 by Qin, T., Barron, L., et al.
PubMed
The effects of transforming growth factor beta (TGF-Ī²) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-Ī² functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-Ī² pathway, we investigated the effect of systemic treatment with a TGF-Ī² inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-Ī² receptor trap, RER, comprised of domains derived from the TGF-Ī² type II and type III receptors. This trap was shown to completely block TĪ²RII binding, to antagonize TGF-Ī²1 and TGF-Ī²3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-Ī² activities than a pan TGF-Ī² neutralizing antibody and a TGF-Ī² receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-Ī² acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-Ī² signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.
Excess TGF-Ī² mediates muscle weakness associated with bone metastases in mice.
In Nature Medicine on 1 November 2015 by Waning, D. L., Mohammad, K. S., et al.
PubMed
Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-Ī², released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-Ī² signaling, TGF-Ī² release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-Ī² activity. Thus, pathological TGF-Ī² release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.
- WB,
- Mus musculus (House mouse),
- Cell Biology
Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration.
In Cell Death & Disease on 30 January 2014 by Zordan, P., Rigamonti, E., et al.
PubMed
The damage of the skeletal muscle prompts a complex and coordinated response that involves the interactions of many different cell populations and promotes inflammation, vascular remodeling and finally muscle regeneration. Muscle disorders exist in which the irreversible loss of tissue integrity and function is linked to defective neo-angiogenesis with persistence of tissue necrosis and inflammation. Here we show that macrophages (MPs) are necessary for efficient vascular remodeling in the injured muscle. In particular, MPs sustain the differentiation of endothelial-derived progenitors to contribute to neo-capillary formation, by secreting pro-angiogenic growth factors. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial to mesenchymal transition (EndoMT), possibly triggered by the activation of transforming growth factor-Ī²/bone morphogenetic protein signaling, collagen accumulates and the muscle is replaced by fibrotic tissue. Our findings provide new insights in EndoMT in the adult skeletal muscle, and suggest that endothelial cells in the skeletal muscle may represent a new target for therapeutic intervention in fibrotic diseases.
- In Vivo,
- Mus musculus (House mouse),
- Immunology and Microbiology
Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells.
In PLoS ONE on 14 June 2013 by Bugaut, H., Bruchard, M., et al.
PubMed
Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP. BLM induces anti-tumor immunity which relies on calreticulin, CD8(+) T cells and interferon-Ī³. We also find that, in addition to its capacity to trigger immunogenic cell death, BLM induces expansion of Foxp3+ regulatory T (Treg) cells via its capacity to induce transforming growth factor beta (TGFĪ²) secretion by tumor cells. Accordingly, Treg cells or TGFĪ² depletion dramatically potentiates the antitumor effect of BLM. We conclude that BLM induces both anti-tumor CD8(+) T cell response and a counteracting Treg proliferation. In the future, TGFĪ² or Treg inhibition during BLM treatment could greatly enhance BLM anti-tumor efficacy.
