InVivoMAb anti-mouse/human/rat/monkey/hamster/canine/bovine TGF-β
Product Details
The 1D11.16.8 monoclonal antibody reacts with mouse, human, rat, monkey, hamster, canine and bovine TGF-β (transforming growth factor beta) isoforms 1, 2 and 3. TGF-β is a multifunctional cytokine that regulates the proliferation of epithelial cells, endothelial cells, fibroblasts, neurons, lymphoid cells including T lymphocytes and NK cells, and other hematopoietic cell types. TGF-β also regulates the activities of activated macrophages and the development of regulatory T cells. Additionally, TGF-β plays roles in immune function, tissue remodeling and wound repair. TGF-β exists as five highly similar isoforms (TGF-β 1-5) with homologies of 70-80%. TGF-β1 is synthesized by the enzymatic cleavage of a long precursor TGF-β1 polypeptide encoded by the TGFB1 gene which yields the mature protein and the Latency Associated Peptide (LAP). The LAP and mature TGF-β1 non-covalently associate during secretion. TGF-β is ubiquitously expressed by many cell types including macrophages and platelets which express high levels of TGF-β. TGF-β signaling has been shown to plays roles in cancer, autoimmune diseases, asthma, heart disease, and diabetes. Its importance is illustrated by TGF-β knockout mice which show defects in hematopoiesis and endothelial differentiation, and die of overwhelming inflammation. The 1D11.16.8 monoclonal antibody is a neutralizing antibody.Specifications
| Isotype | Mouse IgG1, κ |
|---|---|
| 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 | Bovine TGFβ isoform 2 |
| Reported Applications |
in vivo TGFβ neutralization in vitro TGFβ neutralization Western blot |
| Formulation |
PBS, pH 7.0 Contains no stabilizers or preservatives |
| Endotoxin |
<2EU/mg (<0.002EU/μg) Determined by LAL gel clotting assay |
| Purity |
>95% Determined by SDS-PAGE |
| Sterility | 0.2 µm filtration |
| Production | Purified from cell culture supernatant in an animal-free facility |
| Purification | Protein G |
| RRID | AB_1107757 |
| Molecular Weight | 150 kDa |
| Storage | The antibody solution should be stored at the stock concentration at 4°C. Do not freeze. |
Additional Formats
Recommended Products
-
Recommended Isotype Control(s)
InVivoMAb mouse IgG1 isotype control, unknown specificity
-
Recommended Dilution Buffer
InVivoPure pH 7.0 Dilution Buffer
in vivo TGFβ neutralization
Komai, T., et al. (2018). "Transforming Growth Factor-beta and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals" Front Immunol 9: 1364. PubMed
Inhibitory cytokines, such as transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-beta and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited. Here, we show that a combination of TGF-beta and IL-10, but not single cytokine, is required to suppress B cell activation induced by toll-like receptor (TLR) stimulation. In in vivo analyses, the simultaneous presence of TGF-beta and IL-10 effectively suppressed TLR-mediated antigen-specific immune responses and ameliorated pathologies in imiquimod (TLR7 agonist)-induced lupus model and lupus-prone MRL/lpr mice. Intriguingly, TGF-beta and IL-10 synergistically modulated transcriptional programs and suppressed cellular energetics of both glycolysis and oxidative phosphorylation via inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase 1 (S6K1) pathway in TLR-stimulated B cells. On the other hand, enhancement of mTOR signaling and mitochondrial biosynthesis in TLR-stimulated B cells counteracted the synergistic inhibitory effects. The inhibitory cytokine synergy of TGF-beta and IL-10 via suppression of energy metabolism was also observed in human TLR-stimulated B cells. There is increasing evidence supporting the importance of adequate metabolic signals in various immune cells to exert their immune function. In this study, we have shown that a previously unrecognized synergy of inhibitory cytokines regulates systemic humoral immune responses via modulating immunometabolism in B cells. Our findings indicate that inhibition of B cell metabolism mediated by two synergistic cytokines contributes to the induction of immune tolerance and could be a new therapeutic strategy for autoimmune diseases such as systemic lupus erythematosus.
in vivo TGFβ neutralization
Clemente-Casares, X., et al. (2016). "Expanding antigen-specific regulatory networks to treat autoimmunity" Nature 530(7591): 434-440. PubMed
Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.
in vivo TGFβ neutralization
Manlove, L. S., et al. (2015). "Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells" J Immunol . PubMed
BCR-ABL+ acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific Ag that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL+ leukemia progression although ultimately this immune response fails. To address how BCR-ABL+ leukemia escapes immune surveillance, we developed a peptide: MHC class II tetramer that labels endogenous BCR-ABL-specific CD4+ T cells. Naive mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naive BCR-ABL-specific T cells was due to negative selection in the thymus, which depleted BCR-ABL-specific T cells. Consistent with this observation, we saw that BCR-ABL-specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL+ leukemia, BCR-ABL-specific T cells proliferated and converted into regulatory T (Treg) cells, a process that was dependent on cross-reactivity with self-antigen, TGF-beta1, and MHC class II Ag presentation by leukemic cells. Treg cells were critical for leukemia progression in C57BL/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL+ leukemia actively suppresses antileukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells.
in vitro TGFβ neutralization
Bodogai, M., et al. (2015). "Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells" Cancer Res 75(17): 3456-3465. PubMed
Myeloid-derived suppressive cells (MDSC) have been reported to promote metastasis, but the loss of cancer-induced B cells/B regulatory cells (tBreg) can block metastasis despite MDSC expansion in cancer. Here, using multiple murine tumor models and human MDSC, we show that MDSC populations that expand in cancer have only partially primed regulatory function and limited prometastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying, in part, on TgfbetaR1/TgfbetaR2 signaling. MDSC fully educated in this manner exhibit an increased production of reactive oxygen species and NO and more efficiently suppress CD4(+) and CD8(+) T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or TgfbetaR deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regulatory cells are important regulators of the immunosuppressive and prometastatic functions of MDSC.
in vitro TGFβ neutralization
Choi, Y. S., et al. (2015). "LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6" Nat Immunol 16(9): 980-990. PubMed
Follicular helper T cells (TFH cells) are specialized effector CD4(+) T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of TFH cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in TFH cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of TFH cells and the formation of GCs. Forced expression of LEF-1 enhanced TFH differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4(+) T cells to TFH cell signals. Second, they promoted early TFH differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Ralpha and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.
in vivo TGFβ neutralization
Greco, S. H., et al. (2015). "TGF-beta Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia" PLoS One 10(7): e0132786. PubMed
Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-beta) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-beta inhibition using the anti-TGF-beta antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-beta inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.
in vivo TGFβ neutralization
Leon, B., et al. (2014). "FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability" Nat Commun 5: 3495. PubMed
Here, we test the role of FoxP3(+) regulatory T cells (Tregs) in controlling T follicular helper (Tfh) and germinal centre (GC) B-cell responses to influenza. In contrast to the idea that Tregs suppress T-cell responses, we find that Treg depletion severely reduces the Tfh cell response to influenza virus. Furthermore, Treg depletion prevents the accumulation of influenza-specific GCs. These effects are not due to alterations in TGFbeta availability or a precursor-progeny relationship between Tregs and Tfh cells, but are instead mediated by increased availability of IL-2, which suppresses the differentiation of Tfh cells and as a consequence, compromises the GC B response. Thus, Tregs promote influenza-specific GC responses by preventing excessive IL-2 signalling, which suppresses Tfh cell differentiation.
in vivo TGFβ neutralization
Li, W., et al. (2014). "Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis" J Clin Invest 124(2): 755-767. PubMed
TGF-beta is essential for vascular development; however, excess TGF-beta signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-beta overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-beta signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-beta type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-beta and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-beta signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.
in vivo TGFβ neutralization, in vitro TGFβ neutralization
Worthington, J. J., et al. (2013). "Loss of the TGFbeta-activating integrin alphavbeta8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity" PLoS Pathog 9(10): e1003675. PubMed
Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFbeta signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFbeta function results in protection from infection. Mechanistically, we find that enhanced TGFbeta signalling in CD4+ T-cells during infection involves expression of the TGFbeta-activating integrin alphavbeta8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin alphavbeta8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin alphavbeta8-mediated TGFbeta activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin alphavbeta8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.
in vivo TGFβ neutralization
Ring, S., et al. (2013). "Targeting of autoantigens to DEC205(+) dendritic cells in vivo suppresses experimental allergic encephalomyelitis in mice" J Immunol 191(6): 2938-2947. PubMed
The dendritic and epithelial cell receptor with a m.w. of 205 kDa (DEC205) is expressed by dendritic cells (DCs) and facilitates Ag presentation. After injection of Ags coupled to Abs specific for DEC205 into mice, Ag presentation occurs by nonactivated DCs, which leads to induction of regulatory T cells (Tregs). To test this system for tolerance induction in experimental allergic encephalomyelitis (EAE), we created single-chain fragment variables (scFv) specific for DEC205 and fused the scFv to the self-Ag myelin oligodendrocyte glycoprotein (MOG; scFv DEC:MOG). An anti-beta-galactosidase scFv:MOG fusion protein (scFv GL117:MOG) served as isotype control. After staining of DCs in vitro with purified scFv DEC:MOG, binding to DCs and colocalization with MHC class II was apparent, whereas isotype controls did not bind. We next injected scFv DEC:MOG into mice and observed elevated numbers of highly activated, IL-10-producing CD4(+)CD25(+)Foxp3(+) Tregs (17% of CD4) in spleens, as compared with isotype controls and uninjected mice (12% of CD4). Furthermore, DCs isolated from scFv DEC:MOG-injected animals produced significantly increased levels of TGF-beta. Most importantly, when EAE was induced in scFv DEC:MOG-injected mice, 90% of the mice were protected from EAE, whereas all mice in the isotype controls (scFv GL117:MOG) experienced development of EAE. When applying scFv DEC:MOG to mice that had already experienced EAE symptoms, abrogation of the disease in 90% of the animals was apparent, whereas all animals in the control groups experienced development of severe EAE. Thus, these data indicate that targeting of MOG to “steady-state” DCs in vivo may provide a tool to prevent and to treat EAE by a DC/Treg-driven mechanism.
in vitro TGFβ neutralization
Tai, N., et al. (2013). "TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in nonobese diabetic mice" J Immunol 191(6): 2926-2937. PubMed
TLR9-deficient (TLR9(-)/(-)) NOD mice develop a significantly reduced incidence of diabetes. This study was to investigate the molecular mechanisms of the protective role of TLR9 deficiency. Through gene screening and confirmation by both mRNA and protein expression, we found a significant increase in CD73-expressing immune cells from peripheral lymphoid tissues in TLR9(-)/(-) NOD mice. The elevated frequency of CD73-expressing immune cells seemed to be specific for TLR9 deficiency and was MyD88 independent. Moreover, the increased frequency of CD73 expression was limited to the NOD background. Increased frequency of CD73 expression was also associated with lower levels of proinflammatory cytokines and more anti-inflammatory cytokine production in CD4(+) T cells in TLR9(-)/(-) NOD mice. Purified CD73(+)CD4(+) T cells showed stronger immunosuppressive function in vitro and delayed diabetes development in vivo. The immunosuppression appeared to be mediated by TGF-beta. In addition, elevated frequency of CD73-expressing cells was associated with improved beta cell function. Our observations were further confirmed by protection from diabetes with similar alterations in CD73 in the NY8.3 TCR NOD mouse model crossed with TLR9(-)/(-) mice and by the use of a TLR9 inhibitor in NOD mice. Our novel findings suggest an important immune-regulatory role of CD73 in regulation of diabetes development and may offer a new therapeutic strategy for specific intervention to prevent type 1 diabetes.
in vivo TGFβ neutralization
Kurkjian, C., et al. (2012). "Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection" Infect Immun 80(8): 2835-2846. PubMed
Pneumocystis pneumonia was first diagnosed in malnourished children and has more recently been found in children with upper respiratory symptoms. We previously reported that there is a significant delay in the immune response in newborn mice infected with Pneumocystis compared to adults (Garvy BA, Harmsen AG, Infect. Immun. 64:3987-3992, 1996, and Garvy BA, Qureshi M, J. Immunol. 165:6480-6486, 2000). This delay is characterized by the failure of neonatal lungs to upregulate proinflammatory cytokines and attract T cells into the alveoli. Here, we report that regardless of the age at which we infected the mice, they failed to mount an inflammatory response in the alveolar spaces until they were 21 days of age or older. Anti-inflammatory cytokines had some role in dampening inflammation, since interleukin-10 (IL-10)-deficient pups cleared Pneumocystis faster than wild-type pups and the neutralization of transforming growth factor beta (TGF-beta) with specific antibody enhanced T cell migration into the lungs at later time points. However, the clearance kinetics were similar to those of control pups, suggesting that there is an intrinsic deficiency in the ability of innate immunity to control Pneumocystis. We found, using an adoptive transfer strategy, that the lung environment contributes to association of Pneumocystis organisms with alveolar macrophages, implying no intrinsic deficiency in the binding of Pneumocystis by neonatal macrophages. Using both in vivo and in vitro assays, we found that Pneumocystis organisms were less able to stimulate translocation of NF-kappaB to the nucleus of alveolar macrophages from neonatal mice. These data indicate that there is an early unresponsiveness of neonatal alveolar macrophages to Pneumocystis infection that is both intrinsic and related to the immunosuppressive environment found in neonatal lungs.
in vivo TGFβ neutralization
Garidou, L., et al. (2012). "Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection" J Virol 86(13): 7060-7071. PubMed
Persistent viral infections often overburden the immune system and are a major cause of disease in humans. During many persistent infections, antiviral T cells are maintained in a state of immune exhaustion characterized by diminished effector and helper functions. In mammalian systems, an extensive immune regulatory network exists to limit unwanted, potentially fatal immunopathology by inducing T cell exhaustion. However, this regulatory network at times overprotects the host and fosters viral persistence by severely dampening adaptive immune responsiveness. Importantly, recent studies have shown that T cell exhaustion is mediated in part by host immunoregulatory pathways (e.g., programmed death 1 [PD-1], interleukin 10 [IL-10]) and that therapeutic blockade of these pathways either before or during persistent infection can promote viral clearance. Transforming growth factor beta (TGF-beta) is another immunosuppressive cytokine known to impede both self- and tumor-specific T cells, but its role in regulating antiviral immunity is not entirely understood. In this study, we inhibited TGF-beta with three potent antagonists to determine whether neutralization of this regulatory molecule is a viable approach to control a persistent viral infection. Our results revealed that these inhibitors modestly elevate the number of antiviral T cells following infection with a persistent variant of lymphocytic choriomeningitis virus (LCMV) but have no impact on viral clearance. These data suggest that therapeutic neutralization of TGF-beta is not an efficacious means to promote clearance of a persistent viral infection.
- Immunology and Microbiology,
Elimination of Chlamydia muridarum from the female reproductive tract is IL-12p40 dependent, but independent of Th1 and Th2 cells.
In PLoS Pathogens on 1 January 2024 by Rixon, J. A., Fong, K. D., et al.
PubMed
Chlamydia vaccine approaches aspire to induce Th1 cells for optimal protection, despite the fact that there is no direct evidence demonstrating Th1-mediated Chlamydia clearance from the female reproductive tract (FRT). We recently reported that T-bet-deficient mice can resolve primary Chlamydia infection normally, undermining the potentially protective role of Th1 cells in Chlamydia immunity. Here, we show that T-bet-deficient mice develop robust Th17 responses and that mice deficient in Th17 cells exhibit delayed bacterial clearance, demonstrating that Chlamydia-specific Th17 cells represent an underappreciated protective population. Additionally, Th2-deficient mice competently clear cervicovaginal infection. Furthermore, we show that sensing of IFN-γ by non-hematopoietic cells is essential for Chlamydia immunity, yet bacterial clearance in the FRT does not require IFN-γ secretion by CD4 T cells. Despite the fact that Th1 cells are not necessary for Chlamydia clearance, protective immunity to Chlamydia is still dependent on MHC class-II-restricted CD4 T cells and IL-12p40. Together, these data point to IL-12p40-dependent CD4 effector maturation as essential for Chlamydia immunity, and Th17 cells to a lesser extent, yet neither Th1 nor Th2 cell development is critical. Future Chlamydia vaccination efforts will be more effective if they focus on induction of this protective CD4 T cell population. Copyright: © 2024 Rixon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Immunology and Microbiology
Vγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males.
In Nature Communications on 18 July 2023 by Abou-El-Hassan, H., Rezende, R. M., et al.
PubMed
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ-/- mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-β that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI. © 2023. The Author(s).
- Immunology and Microbiology
Low-dose radiation therapy suppresses viral pneumonia by enhancing broad-spectrum anti-inflammatory responses via transforming growth factor-β production.
In Frontiers in Immunology on 12 June 2023 by Song, H. Y., Chen, F., et al.
PubMed
Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid arthritis patients annually in Europe. Several recent clinical trials have reported that LDRT can effectively reduce the severity of coronavirus disease (COVID-19) and other cases of viral pneumonia. However, the therapeutic mechanism of LDRT remains unelucidated. Therefore, in the current study, we aimed to investigate the molecular mechanism underlying immunological alterations in influenza pneumonia after LDRT. Mice were irradiated to the whole lung 1 day post-infection. The changes in levels of inflammatory mediators (cytokines and chemokines) and immune cell populations in the bronchoalveolar lavage (BALF), lungs, and serum were examined. LDRT-treated mice displayed markedly increased survival rates and reduced lung edema and airway and vascular inflammation in the lung; however, the viral titers in the lungs were unaffected. Levels of primary inflammatory cytokines were reduced after LDRT, and transforming growth factor-β (TGF-β) levels increased significantly on day 1 following LDRT. Levels of chemokines increased from day 3 following LDRT. Additionally, M2 macrophage polarization or recruitment was increased following LDRT. We found that LDRT-induced TGF-β reduced the levels of cytokines and polarized M2 cells and blocked immune cell infiltration, including neutrophils, in BALF. LDRT-induced early TGF-β production was shown to be a key regulator involved in broad-spectrum anti-inflammatory activity in virus-infected lungs. Therefore, LDRT or TGF-β may be an alternative therapy for viral pneumonia. Copyright © 2023 Song, Chen, Park, Han, Ji, Byun, Kwon, Kim, Ahn and Seo.
- Cancer Research,
- Endocrinology and Physiology,
- Neuroscience
Schwann cell insulin-like growth factor receptor type-1 mediates metastatic bone cancer pain in mice.
In Brain, Behavior, and Immunity on 1 May 2023 by Landini, L., Marini, M., et al.
PubMed
Insulin growth factor-1 (IGF-1), an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain (MBCP), but the underlying mechanism is poorly understood. In mice, the femur metastasis caused by intramammary inoculation of breast cancer cells resulted in IGF-1 increase in femur and sciatic nerve, and IGF-1-dependent stimulus/non-stimulus-evoked pain-like behaviors. Adeno-associated virus-based shRNA selective silencing of IGF-1 receptor (IGF-1R) in Schwann cells, but not in dorsal root ganglion (DRG) neurons, attenuated pain-like behaviors. Intraplantar IGF-1 evoked acute nociception and mechanical/cold allodynia, which were reduced by selective IGF-1R silencing in DRG neurons and Schwann cells, respectively. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated transient receptor potential ankyrin 1 (TRPA1) activation and release of reactive oxygen species that, via macrophage-colony stimulating factor-dependent endoneurial macrophage expansion, sustained pain-like behaviors. Osteoclast derived IGF-1 initiates a Schwann cell-dependent neuroinflammatory response that sustains a proalgesic pathway that provides new options for MBCP treatment. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
- In Vivo,
- Mus musculus (House mouse),
- Cancer Research
Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation.
In Cancer Cell on 10 April 2023 by Mousset, A., Lecorgne, E., et al.
PubMed
Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1β, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-αvβ1, which traps latent TGF-β, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-β. TGF-β activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1β-NET-TGF-β axis. Copyright © 2023 Elsevier Inc. All rights reserved.
Preventing Surgery-Induced NK Cell Dysfunction Using Anti-TGF-β Immunotherapeutics.
In International Journal of Molecular Sciences on 23 November 2022 by Market, M., Tennakoon, G., et al.
PubMed
Natural Killer (NK) cell cytotoxicity and interferon-gamma (IFNγ) production are profoundly suppressed postoperatively. This dysfunction is associated with increased morbidity and cancer recurrence. NK activity depends on the integration of activating and inhibitory signals, which may be modulated by transforming growth factor-beta (TGF-β). We hypothesized that impaired postoperative NK cell IFNγ production is due to altered signaling pathways caused by postoperative TGF-β. NK cell receptor expression, downstream phosphorylated targets, and IFNγ production were assessed using peripheral blood mononuclear cells (PBMCs) from patients undergoing cancer surgery. Healthy NK cells were incubated in the presence of healthy/baseline/postoperative day (POD) 1 plasma and in the presence/absence of a TGF-β-blocking monoclonal antibody (mAb) or the small molecule inhibitor (smi) SB525334. Single-cell RNA sequencing (scRNA-seq) was performed on PBMCs from six patients with colorectal cancer having surgery at baseline/on POD1. Intracellular IFNγ, activating receptors (CD132, CD212, NKG2D, DNAM-1), and downstream target (STAT5, STAT4, p38 MAPK, S6) phosphorylation were significantly reduced on POD1. Furthermore, this dysfunction was phenocopied in healthy NK cells through incubation with rTGF-β1 or POD1 plasma and was prevented by the addition of anti-TGF-β immunotherapeutics (anti-TGF-β mAb or TGF-βR smi). Targeted gene analysis revealed significant decreases in S6 and FKBP12, an increase in Shp-2, and a reduction in NK metabolism-associated transcripts on POD1. pSmad2/3 was increased and pS6 was reduced in response to rTGF-β1 on POD1, changes that were prevented by anti-TGF-β immunotherapeutics. Together, these results suggest that both canonical and mTOR pathways downstream of TGF-β mediate phenotypic changes that result in postoperative NK cell dysfunction.
- IHC,
- WB,
- Homo sapiens (Human),
- Cell Biology
Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells.
In Cell Death & Disease on 17 November 2022 by Bontempi, G., Terri, M., et al.
PubMed
Histone acetylation/deacetylation play an essential role in modifying chromatin structure and in regulating cell plasticity in eukaryotic cells. Therefore, histone deacetylase (HDAC) pharmacological inhibitors are promising tools in the therapy of fibrotic diseases and in cancer. Peritoneal fibrosis is a pathological process characterized by many cellular and molecular alterations, including the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT). The aim of this study was to characterize the molecular mechanism of the antifibrotic role of HDAC1 inhibition. Specifically, treatment with MS-275, an HDAC1-3 inhibitor previously known to promote MMT reversal, induced the expression of several TGFBRI mRNA-targeting miRNAs. Among them, miR-769-5p ectopic expression was sufficient to promote MMT reversal and to limit MC migration and invasion, whereas miR-769-5p silencing further enhanced mesenchymal gene expression. These results were confirmed by HDAC1 genetic silencing. Interestingly, miR-769-5p silencing maintained mesenchymal features despite HDAC1 inhibition, thus indicating that it is necessary to drive MMT reversal induced by HDAC1 inhibition. Besides TGFBRI, miR-769-5p was demonstrated to target SMAD2/3 and PAI-1 expression directly. When analyzing molecular mechanisms underlying miR-769-5p expression, we found that the transcription factor Wilms' tumor 1 (WT1), a master gene controlling MC development, binds to the miR-769-5p promoter favoring its expression. Interestingly, both WT1 expression and binding to miR-769-5p promoter were increased by HDAC1 inhibition and attenuated by TGFβ1 treatment. Finally, we explored the significance of these observations in the cell-to-cell communication: we evaluated the ability of miR-769-5p to be loaded into extracellular vesicles (EVs) and to promote MMT reversal in recipient mesenchymal-like MCs. Treatment of fibrotic MCs with EVs isolated from miR-769-5p over-expressing MCs promoted the down-regulation of specific mesenchymal targets and the reacquisition of an epithelial-like morphology. In conclusion, we highlighted an HDAC1-WT1-miR-769-5p axis potentially relevant for therapies aimed at counteracting organ fibrosis. © 2022. The Author(s).
- Cancer Research,
- Neuroscience
Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity.
In Brain on 14 September 2022 by Perelroizen, R., Philosof, B., et al.
PubMed
Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
- Cancer Research,
- Immunology and Microbiology
Induction of tumor cell autosis by myxoma virus-infected CAR-T and TCR-T cells to overcome primary and acquired resistance.
In Cancer Cell on 12 September 2022 by Zheng, N., Fang, J., et al.
PubMed
Cytotoxicity of tumor-specific T cells requires tumor cell-to-T cell contact-dependent induction of classic tumor cell apoptosis and pyroptosis. However, this may not trigger sufficient primary responses of solid tumors to adoptive cell therapy or prevent tumor antigen escape-mediated acquired resistance. Here we test myxoma virus (MYXV)-infected tumor-specific T (TMYXV) cells expressing chimeric antigen receptor (CAR) or T cell receptor (TCR), which systemically deliver MYXV into solid tumors to overcome primary resistance. In addition to T cell-induced apoptosis and pyroptosis, tumor eradication by CAR/TCR-TMYXV cells is also attributed to tumor cell autosis induction, a special type of cell death. Mechanistically, T cell-derived interferon γ (IFNγ)-protein kinase B (AKT) signaling synergizes with MYXV-induced M-T5-SKP-1-VPS34 signaling to trigger robust tumor cell autosis. CAR/TCR-TMYXV-elicited autosis functions as a type of potent bystander killing to restrain antigen escape. We uncover an unexpected synergy between T cells and MYXV to bolster solid tumor cell autosis that reinforces tumor clearance. Copyright © 2022 Elsevier Inc. All rights reserved.
- Immunology and Microbiology
Enterobacter ludwigii protects DSS-induced colitis through choline-mediated immune tolerance.
In Cell Reports on 30 August 2022 by Li, Q., Sun, X., et al.
PubMed
Commensal intestinal bacteria play key roles in regulating host immune tolerance; however, bacterial strains and related metabolites directly involved in this regulation are largely unknown. Here, using a mouse model of dextran sulfate sodium (DSS)-induced colitis combined with different antibiotic treatment, Enterobacter ludwigii, abundant in microbiota of mice treated with metronidazole, is screened out to have prophylactic and therapeutic effects on DSS-induced colitis with or without the presence of complex intestinal bacteria. E. ludwigii is found to induce CD103+DC and regulatory T (Treg)-mediated immune tolerance for colitis remission using in vitro and in vivo experiments. Moreover, choline, one metabolite of E. ludwigii, is identified to increase dendritic cells' (DCs) immune tolerance to promote Treg differentiation. E. ludwigii is found to induce DCs' immune tolerance ability for Treg differentiation through choline and α7nAChR-mediated retinoic acid (RA) and transforming growth factor beta (TGF-β) upregulation, resulting in protecting mice against DSS-induced colitis. This study suggests potential therapeutic approaches for inflammatory bowel diseases (IBDs).Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Low-dose interleukin-2 reverses chronic migraine-related sensitizations through peripheral interleukin-10 and transforming growth factor beta-1 signaling.
In Neurobiology of Pain (Elsevier) on 24 June 2022 by Guo, Z., Zhang, J., et al.
PubMed
Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2. Indeed, neutralizing antibodies against either IL-10 or TGFβ completely blocked the effects of LD-IL-2 on the facial mechanical hypersensitivity as well as the sensitization of TG neurons resulting from repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration in mice, indicating that LD-IL-2 and Treg cells engage both peripheral IL-10 and TGFβ signaling pathways to reverse chronic-migraine related sensitizations. In an in vitro assay, incubation of TG culture with exogenous IL-10 or TGFβ1 fully reversed NTG-induced sensitization of TG neurons, suggesting that the IL-10 and TGFβ1 signaling in TG neurons contribute to LD-IL-2's therapeutic effects. Collectively, these results not only elucidate the molecular mechanisms through which LD-IL-2 and Treg cells reverse chronic-migraine related sensitizations, but also suggest that the IL-10 and TGFβ1 signaling pathways in TG neurons are potential targets for chronic migraine therapy. © 2022 The Author(s).
- Biochemistry and Molecular biology,
- Cancer Research,
- Immunology and Microbiology
Human Melanoma-Associated Mast Cells Display a Distinct Transcriptional Signature Characterized by an Upregulation of the Complement Component 3 That Correlates With Poor Prognosis.
In Frontiers in Immunology on 8 June 2022 by Bahri, R., Kiss, O., et al.
PubMed
Cutaneous melanoma is one of the most aggressive human malignancies and shows increasing incidence. Mast cells (MCs), long-lived tissue-resident cells that are particularly abundant in human skin where they regulate both innate and adaptive immunity, are associated with melanoma stroma (MAMCs). Thus, MAMCs could impact melanoma development, progression, and metastasis by secreting proteases, pro-angiogenic factors, and both pro-inflammatory and immuno-inhibitory mediators. To interrogate the as-yet poorly characterized role of human MAMCs, we have purified MCs from melanoma skin biopsies and performed RNA-seq analysis. Here, we demonstrate that MAMCs display a unique transcriptome signature defined by the downregulation of the FcεRI signaling pathway, a distinct expression pattern of proteases and pro-angiogenic factors, and a profound upregulation of complement component C3. Furthermore, in melanoma tissue, we observe a significantly increased number of C3+ MCs in stage IV melanoma. Moreover, in patients, C3 expression significantly correlates with the MC-specific marker TPSAB1, and the high expression of both markers is linked with poorer melanoma survival. In vitro, we show that melanoma cell supernatants and tumor microenvironment (TME) mediators such as TGF-β, IL-33, and IL-1β induce some of the changes found in MAMCs and significantly modulate C3 expression and activity in MCs. Taken together, these data suggest that melanoma-secreted cytokines such as TGF-β and IL-1β contribute to the melanoma microenvironment by upregulating C3 expression in MAMCs, thus inducing an MC phenotype switch that negatively impacts melanoma prognosis. Copyright © 2022 Bahri, Kiss, Prise, Garcia-Rodriguez, Atmoko, Martínez-Gómez, Levesque, Dummer, Smith, Wellbrock and Bulfone-Paus.
- Cancer Research,
- Immunology and Microbiology,
- In Vivo,
- Mus musculus (House mouse)
Lymph node colonization induces tumor-immune tolerance to promote distant metastasis.
In Cell on 26 May 2022 by Reticker-Flynn, N. E., Zhang, W., et al.
PubMed
For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs. Copyright © 2022 Elsevier Inc. All rights reserved.
- Neutralization,
- Mus musculus (House mouse),
- Immunology and Microbiology
A neutrophil/TGF-β axis limits the pathogenicity of allergen-specific CD4+ T cells.
In JCI Insight on 22 February 2022 by Whitehead, G. S., Thomas, S. Y., et al.
PubMed
The intensity and longevity of inflammatory responses to inhaled allergens is determined largely by the balance between effector and regulatory immune responses, but the mechanisms that determine the relative magnitudes of these opposing forces remain poorly understood. We have found that the type of adjuvant used during allergic sensitization has a profound effect on both the nature and longevity of the pulmonary inflammation triggered by subsequent reexposure to that same provoking allergen. TLR ligand adjuvants and house dust extracts primed immune responses characterized by a mixed neutrophilic and eosinophilic inflammation that was suppressed by multiple daily allergen challenges. During TLR ligand-mediated allergic sensitization, mice displayed transient airway neutrophilia, which triggered the release of TGF-β into the airway. This neutrophil-dependent production of TGF-β during sensitization had a delayed, suppressive effect on eosinophilic responses to subsequent allergen challenge. Neutrophil depletion during sensitization did not affect numbers of Foxp3+ Tregs but increased proportions of Gata3+CD4+ T cells, which, upon their transfer to recipient mice, triggered stronger eosinophilic inflammation. Thus, a neutrophil/TGF-β axis acts during TLR-mediated allergic sensitization to fine-tune the phenotype of developing allergen-specific CD4+ T cells and limit their pathogenicity, suggesting a novel immunotherapeutic approach to control eosinophilia in asthma.
- Immunology and Microbiology
CD1dhiPD-L1hiCD27+ Regulatory Natural Killer Subset Suppresses Atopic Dermatitis.
In Frontiers in Immunology on 25 January 2022 by Min, K. Y., Koo, J., et al.
PubMed
Effector and regulatory functions of various leukocytes in allergic diseases have been well reported. Although the role of conventional natural killer (NK) cells has been established, information on its regulatory phenotype and function are very limited. Therefore, the objective of this study was to investigate the phenotype and inhibitory functions of transforming growth factor (TGF)-β-producing regulatory NK (NKreg) subset in mice with MC903-induced atopic dermatitis (AD). Interestingly, the population of TGF-β-producing NK cells in peripheral blood monocytes (PBMCs) was decreased in AD patients than in healthy subjects. The number of TGF-β+ NK subsets was decreased in the spleen or cervical lymph node (cLN), but increased in ear tissues of mice with AD induced by MC903 than those of normal mice. We further observed that TGF-β+ NK subsets were largely included in CD1dhiPD-L1hiCD27+ NK cell subset. We also found that numbers of ILC2s and TH2 cells were significantly decreased by adoptive transfer of CD1dhiPD-L1hiCD27+ NK subsets. Notably, the ratio of splenic Treg per TH2 was increased by the adoptive transfer of CD1dhiPD-L1hiCD27+ NK cells in mice. Taken together, our findings demonstrate that the TGF-β-producing CD1dhiPD-L1hiCD27+ NK subset has a previously unrecognized role in suppressing TH2 immunity and ILC2 activation in AD mice, suggesting that the function of TGF-β-producing NK subset is closely associated with the severity of AD in humans. Copyright © 2022 Min, Koo, Noh, Lee, Jo, Lee, Kang, Hyun, Choi and Kim.
- Cardiovascular biology
Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction.
In Nature Communications on 10 January 2022 by Vukicevic, S., Colliva, A., et al.
PubMed
Despite the high prevalence of ischemic heart diseases worldwide, no antibody-based treatment currently exists. Starting from the evidence that a specific isoform of the Bone Morphogenetic Protein 1 (BMP1.3) is particularly elevated in both patients and animal models of myocardial infarction, here we assess whether its inhibition by a specific monoclonal antibody reduces cardiac fibrosis. We find that this treatment reduces collagen deposition and cross-linking, paralleled by enhanced cardiomyocyte survival, both in vivo and in primary cultures of cardiac cells. Mechanistically, we show that the anti-BMP1.3 monoclonal antibody inhibits Transforming Growth Factor β pathway, thus reducing myofibroblast activation and inducing cardioprotection through BMP5. Collectively, these data support the therapeutic use of anti-BMP1.3 antibodies to prevent cardiomyocyte apoptosis, reduce collagen deposition and preserve cardiac function after ischemia. © 2022. The Author(s).
- Endocrinology and Physiology,
- Neuroscience
Inhibition of TGF-β Signaling Attenuates Disuse-induced Trabecular Bone Loss After Spinal Cord Injury in Male Mice.
In Endocrinology on 1 January 2022 by Sahbani, K., Cardozo, C. P., et al.
PubMed
Bone loss is one of the most common complications of immobilization after spinal cord injury (SCI). Whether transforming growth factor (TGF)-β signaling plays a role in SCI-induced disuse bone loss has not been determined. Thus, 16-week-old male mice underwent sham or spinal cord contusion injury to cause complete hindlimb paralysis. Five days later, 10 mg/kg/day control (IgG) or anti-TGF-β1,2,3 neutralizing antibody (1D11) was administered twice weekly for 4 weeks. Femurs were examined by micro-computed tomography (micro-CT) scanning and histology. Bone marrow (BM) supernatants were analyzed by enzyme-linked immunosorbent assay for levels of procollagen type 1 intact N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase (TRAcP-5b), receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), and prostaglandin E2 (PGE2). Distal femoral micro-CT analysis showed that SCI-1D11 mice had significantly (P < .05) attenuated loss of trabecular fractional bone volume (123% SCI-1D11 vs 69% SCI-IgG), thickness (98% vs 81%), and connectivity (112% vs 69%) and improved the structure model index (2.1 vs 2.7). Histomorphometry analysis revealed that osteoclast numbers were lower in the SCI-IgG mice than in sham-IgG control. Biochemically, SCI-IgG mice had higher levels of P1NP and PGE2 but similar TRAcP-5b and RANKL/OPG ratio to the sham-IgG group. The SCI-1D11 group exhibited higher levels of P1NP but similar TRAcP-5b, RANKL/OPG ratio, and PGE2 to the sham-1D11 group. Furthermore, 1D11 treatment prevented SCI-induced hyperphosphorylation of tau protein in osteocytes, an event that destabilizes the cytoskeleton. Together, inhibition of TGF-β signaling after SCI protects trabecular bone integrity, likely by balancing bone remodeling, inhibiting PGE2 elevation, and preserving the osteocyte cytoskeleton. Published by Oxford University Press on behalf of the Endocrine Society 2021.
- Cancer Research
Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer.
In Cancer Communications (London, England) on 1 January 2022 by Cheng, B., Ding, K., et al.
PubMed
Second-generation programmed cell death-protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, such as bintrafusp alfa (M7824), SHR-1701, and YM101, have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor (TGF-β/TGF-βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors. Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor-infiltrating immune cells. For lung cancer patients treated with anti-PD-1/PD-L1 antibodies, poor lymphocyte recovery was associated with a shorter progression-free survival (PFS; P 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8+ T cells in the peripheral blood. Levels of CD8+ T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-L1/TGF-βR fusion protein (SHR-1701). Consistently, SHR-1701 but not anti-PD-1 antibodies, markedly enhanced IFN-γ production and Ki-67 expression in peripheral CD8+ T cells from patients with impaired lymphocyte recovery. Lung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701. © 2022 The Authors. Cancer Communications published by John Wiley Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.
- Immunology and Microbiology
Intestinal CD11b+ B Cells Ameliorate Colitis by Secreting Immunoglobulin A.
In Frontiers in Immunology on 23 November 2021 by Fu, Y., Wang, Z., et al.
PubMed
The intestinal mucosal immune environment requires multiple immune cells to maintain homeostasis. Although intestinal B cells are among the most important immune cells, little is known about the mechanism that they employ to regulate immune homeostasis. In this study, we found that CD11b+ B cells significantly accumulated in the gut lamina propria and Peyer's patches in dextran sulfate sodium-induced colitis mouse models and patients with ulcerative colitis. Adoptive transfer of CD11b+ B cells, but not CD11b-/- B cells, effectively ameliorated colitis and exhibited therapeutic effects. Furthermore, CD11b+ B cells were found to produce higher levels of IgA than CD11b- B cells. CD11b deficiency in B cells dampened IgA production, resulting in the loss of their ability to ameliorate colitis. Mechanistically, CD11b+ B cells expressed abundant TGF-β and TGF-β receptor II, as well as highly activate phosphorylated Smad2/3 signaling pathway, consequently promoting the class switch to IgA. Collectively, our findings demonstrate that CD11b+ B cells are essential intestinal suppressive immune cells and the primary source of intestinal IgA, which plays an indispensable role in maintaining intestinal homeostasis. Copyright © 2021 Fu, Wang, Yu, Lin, Huang, Liu, Zhao, Lu, Xu, Liu, Liu, Wang and Chu.
- Cancer Research,
- Immunology and Microbiology
Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.
In IScience on 19 November 2021 by Gabriely, G., Ma, D., et al.
PubMed
Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.© 2021 The Authors.