InVivoMAb mouse IgG1 isotype control, unknown specificity
Product Details
The MOPC-21 monoclonal antibody is ideal for use as a non-reactive isotype-matched control for mouse IgG1 antibodies in most in vivo and in vitro applications.Specifications
| Isotype | Mouse IgG1,Ā Īŗ |
|---|---|
| Recommended Dilution Buffer | InVivoPure pH 6.5 Dilution Buffer |
| Conjugation | This product is unconjugated. Conjugation is available via our Antibody Conjugation Services. |
| Formulation |
PBS, pH 6.5 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 Āµm filtration |
| Production | Purified from cell culture supernatant in an animal-free facility |
| Purification | Protein G |
| RRID | AB_1107784 |
| Molecular Weight | 150 kDa |
| Storage | The antibody solution should be stored at the stock concentration at 4Ā°C. Do not freeze. |
Additional Formats
Recommended Products
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Recommended Dilution Buffer
InVivoPure pH 6.5 Dilution Buffer
Faraco, G., et al. (2018). "Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response" Nat Neurosci 21(2): 240-249. PubMed
A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.
Macal, M., et al. (2018). "Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection" Immunity 48(4): 730-744 e735. PubMed
Although characterization of T cell exhaustion has unlocked powerful immunotherapies, the mechanisms sustaining adaptations of short-lived innate cells to chronic inflammatory settings remain unknown. During murine chronic viral infection, we found that concerted events in bone marrow and spleen mediated by type I interferon (IFN-I) and Toll-like receptor 7 (TLR7) maintained a pool of functionally exhausted plasmacytoid dendritic cells (pDCs). In the bone marrow, IFN-I compromised the number and the developmental capacity of pDC progenitors, which generated dysfunctional pDCs. Concurrently, exhausted pDCs in the periphery were maintained by self-renewal via IFN-I- and TLR7-induced proliferation of CD4(-) subsets. On the other hand, pDC functional loss was mediated by TLR7, leading to compromised IFN-I production and resistance to secondary infection. These findings unveil the mechanisms sustaining a self-perpetuating pool of functionally exhausted pDCs and provide a framework for deciphering long-term exhaustion of other short-lived innate cells during chronic inflammation.
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.
Sell, S., et al. (2015). "Control of murine cytomegalovirus infection by gammadelta T cells" PLoS Pathog 11(2): e1004481. PubMed
Infections with cytomegalovirus (CMV) can cause severe disease in immunosuppressed patients and infected newborns. Innate as well as cellular and humoral adaptive immune effector functions contribute to the control of CMV in immunocompetent individuals. None of the innate or adaptive immune functions are essential for virus control, however. Expansion of gammadelta T cells has been observed during human CMV (HCMV) infection in the fetus and in transplant patients with HCMV reactivation but the protective function of gammadelta T cells under these conditions remains unclear. Here we show for murine CMV (MCMV) infections that mice that lack CD8 and CD4 alphabeta-T cells as well as B lymphocytes can control a MCMV infection that is lethal in RAG-1(-/-) mice lacking any T- and B-cells. gammadelta T cells, isolated from infected mice can kill MCMV infected target cells in vitro and, importantly, provide long-term protection in infected RAG-1(-/-) mice after adoptive transfer. gammadelta T cells in MCMV infected hosts undergo a prominent and long-lasting phenotypic change most compatible with the view that the majority of the gammadelta T cell population persists in an effector/memory state even after resolution of the acute phase of the infection. A clonotypically focused Vgamma1 and Vgamma2 repertoire was observed at later stages of the infection in the organs where MCMV persists. These findings add gammadelta T cells as yet another protective component to the anti-CMV immune response. Our data provide clear evidence that gammadelta T cells can provide an effective control mechanism of acute CMV infections, particularly when conventional adaptive immune mechanisms are insufficient or absent, like in transplant patient or in the developing immune system in utero. The findings have implications in the stem cell transplant setting, as antigen recognition by gammadelta T cells is not MHC-restricted and dual reactivity against CMV and tumors has been described.
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.
Beug, S. T., et al. (2014). "Smac mimetics and innate immune stimuli synergize to promote tumor death" Nat Biotechnol 32(2): 182-190. PubMed
Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe ācytokine storm.ā Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-beta), tumor necrosis factor alpha (TNF-alpha) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.
Perng, O. A., et al. (2014). "The degree of CD4+ T cell autoreactivity determines cellular pathways underlying inflammatory arthritis" J Immunol 192(7): 3043-3056. PubMed
Although therapies targeting distinct cellular pathways (e.g., anticytokine versus anti-B cell therapy) have been found to be an effective strategy for at least some patients with inflammatory arthritis, the mechanisms that determine which pathways promote arthritis development are poorly understood. We have used a transgenic mouse model to examine how variations in the CD4(+) T cell response to a surrogate self-peptide can affect the cellular pathways that are required for arthritis development. CD4(+) T cells that are highly reactive with the self-peptide induce inflammatory arthritis that affects male and female mice equally. Arthritis develops by a B cell-independent mechanism, although it can be suppressed by an anti-TNF treatment, which prevented the accumulation of effector CD4(+) Th17 cells in the joints of treated mice. By contrast, arthritis develops with a significant female bias in the context of a more weakly autoreactive CD4(+) T cell response, and B cells play a prominent role in disease pathogenesis. In this setting of lower CD4(+) T cell autoreactivity, B cells promote the formation of autoreactive CD4(+) effector T cells (including Th17 cells), and IL-17 is required for arthritis development. These studies show that the degree of CD4(+) T cell reactivity for a self-peptide can play a prominent role in determining whether distinct cellular pathways can be targeted to prevent the development of inflammatory arthritis.
Vokaer, B., et al. (2013). "IL-17A and IL-2-expanded regulatory T cells cooperate to inhibit Th1-mediated rejection of MHC II disparate skin grafts" PLoS One 8(10): e76040. PubMed
Several evidences suggest that regulatory T cells (Treg) promote Th17 differentiation. Based on this hypothesis, we tested the effect of IL-17A neutralization in a model of skin transplantation in which long-term graft survival depends on a strong in vivo Treg expansion induced by transient exogenous IL-2 administration. As expected, IL-2 supplementation prevented rejection of MHC class II disparate skin allografts but, surprisingly, not in IL-17A-deficient recipients. We attested that IL-17A was not required for IL-2-mediated Treg expansion, intragraft recruitment or suppressive capacities. Instead, IL-17A prevented allograft rejection by inhibiting Th1 alloreactivity independently of Tregs. Indeed, T-bet expression of naive alloreactive CD4+ T cells and the subsequent Th1 immune response was significantly enhanced in IL-17A deficient mice. Our results illustrate for the first time a protective role of IL-17A in CD4+-mediated allograft rejection process.
Kerzerho, J., et al. (2013). "Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity" J Allergy Clin Immunol 131(4): 1048-1057, 1057 e1041-1042. PubMed
BACKGROUND: Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood. OBJECTIVE: The aim of this study was to determine whether TH9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development. METHOD: We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of TH9 development in vivo. RESULTS: TH9 cells were detectable in the lungs after chronic allergen exposure. The number of TH9 cells directly correlated with the severity of AHR, and anti-IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of TH9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-beta and IL-1alpha levels in the lungs, enhanced pulmonary TH9 differentiation, and higher morbidity in the sensitized mice. CONCLUSION: Our findings suggest that PD-L2 plays a pivotal role in the regulation of TH9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses.
Myles, I. A., et al. (2013). "Signaling via the IL-20 receptor inhibits cutaneous production of IL-1beta and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus" Nat Immunol 14(8): 804-811. PubMed
Staphylococcus aureus causes most infections of human skin and soft tissue and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin 19 (IL-19), IL-20 and IL-24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We found here that those cytokines promoted cutaneous infection with S. aureus in mice by downregulating IL-1beta- and IL-17A-dependent pathways. We noted similar effects of those cytokines in human keratinocytes after exposure to S. aureus, and antibody blockade of the IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for IL-19, IL-20 and IL-24 during infection that could be therapeutically targeted to alter susceptibility to infection.
Lamere, M. W., et al. (2011). "Regulation of antinucleoprotein IgG by systemic vaccination and its effect on influenza virus clearance" J Virol 85(10): 5027-5035. PubMed
Seasonal influenza epidemics recur due to antigenic drift of envelope glycoprotein antigens and immune evasion of circulating viruses. Additionally, antigenic shift can lead to influenza pandemics. Thus, a universal vaccine that protects against multiple influenza virus strains could alleviate the continuing impact of this virus on human health. In mice, accelerated clearance of a new viral strain (cross-protection) can be elicited by prior infection (heterosubtypic immunity) or by immunization with the highly conserved internal nucleoprotein (NP). Both heterosubtypic immunity and NP-immune protection require antibody production. Here, we show that systemic immunization with NP readily accelerated clearance of a 2009 pandemic H1N1 influenza virus isolate in an antibody-dependent manner. However, human immunization with trivalent inactivated influenza virus vaccine (TIV) only rarely and modestly boosted existing levels of anti-NP IgG. Similar results were observed in mice, although the reaction could be enhanced with adjuvants, by adjusting the stoichiometry among NP and other vaccine components, and by increasing the interval between TIV prime and boost. Importantly, mouse heterosubtypic immunity that had waned over several months could be enhanced by injecting purified anti-NP IgG or by boosting with NP protein, correlating with a long-lived increase in anti-NP antibody titers. Thus, current immunization strategies poorly induce NP-immune antibody that is nonetheless capable of contributing to long-lived cross-protection. The high conservation of NP antigen and the known longevity of antibody responses suggest that the antiviral activity of anti-NP IgG may provide a critically needed component of a universal influenza vaccine.
- Immunology and Microbiology,
Mucosal unadjuvanted booster vaccines elicit local IgA responses by conversion of pre-existing immunity in mice.
In Nature Immunology on 1 June 2025 by Kwon, D. I., Mao, T., et al.
Mucosal delivery of vaccine boosters induces robust local protective immune responses even without any adjuvants. Yet, the mechanisms by which antigen alone induces mucosal immunity in the respiratory tract remain unclear. Here we show that an intranasal booster with an unadjuvanted recombinant SARS-CoV-2 spike protein, after intramuscular immunization with 1āĪ¼g of mRNA-LNP vaccine encoding the full-length SARS-CoV-2 spike protein (Pfizer/BioNTech BNT162b2), elicits protective mucosal immunity by retooling the lymph node-resident immune cells. On intranasal boosting, peripheral lymph node-primed B cells rapidly migrated to the lung through CXCR3-CXCL9 and CXCR3-CXCL10 signaling and differentiated into antigen-specific IgA-secreting plasma cells. Memory CD4+ T cells in the lung served as a natural adjuvant for developing mucosal IgA by inducing the expression of chemokines CXCL9 and CXCL10 for memory B cell recruitment. Furthermore, CD40 and TGFĪ² signaling had important roles in mucosal IgA development. Repeated mucosal boosting with an unadjuvanted protein amplified anamnestic IgA responses in both the upper and the lower respiratory tracts. These findings help explain why nasal boosters do not require an adjuvant to induce robust mucosal immunity at the respiratory mucosa and can be used to design safe and effective vaccines against respiratory pathogens. Ā© 2025. The Author(s).
Integrin-mediated mTOR signaling drives TGF-Ī² overactivity and myxomatous mitral valve degeneration in hypomorphic fibrillin-1 mice.
In The Journal of Clinical Investigation on 20 May 2025 by Gao, F., Chen, Q., et al.
Mitral valve prolapse is often benign but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic FBN1 variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-Ī² and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-Ī² overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-Ī² signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell-matrix interactions drives TGF-Ī² overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.
- Cancer Research
NECTIN4 regulates the cell surface expression of CD155 in non-small cell lung cancer cells and induces tumor resistance to PD-1 inhibitors.
In Cancer Immunology, Immunotherapy : CII on 20 May 2025 by Mizusaki, S., Yoneshima, Y., et al.
The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT. Ā© 2025. The Author(s).
- Immunology and Microbiology
Type I interferon drives T cell cytotoxicity by upregulation of interferon regulatory factor 7 in autoimmune kidney diseases in mice.
In Nature Communications on 20 May 2025 by Wang, H., Engesser, J., et al.
In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases. Ā© 2025. The Author(s).
- Cell Biology,
- Immunology and Microbiology
Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
In Nature Communications on 20 May 2025 by VanPortfliet, J. J., Lei, Y., et al.
Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD. Ā© 2025. The Author(s).
Type I interferon signaling controls the early hematopoietic expansion in response to Ī²-glucan.
In IScience on 16 May 2025 by Xu, Y., Lee, M. K. S., et al.
Rapid hematopoietic adaptations are important for building and sustaining the biological response to Ī²-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to Ī²-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to Ī²-glucan. InĀ vivo administration of Ī²-glucan led to local interferon-Ī± production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for Ī²-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to Ī²-glucan. Ā© 2025 The Author(s).
- Biochemistry and Molecular biology,
- Cell Biology,
- Genetics,
- Immunology and Microbiology
TIGIT deficiency promotes autoreactive CD4+ T-cell responses through a metabolicāepigenetic mechanism in autoimmune myositis.
In Nature Communications on 15 May 2025 by Lai, Y., Wang, S., et al.
Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells' differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolicāepigenetic reprogramming, with important implications for treating systemic autoimmune diseases. Ā© 2025. The Author(s).
The gut microbiome controls reactive astrocytosis during AĪ² amyloidosis via propionate-mediated regulation of IL-17.
In The Journal of Clinical Investigation on 13 May 2025 by Chandra, S., PopoviÄ, J., et al.
Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer's disease (AD). We recently showed that the GMB regulates reactive astrocytosis and AĪ² plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces AĪ² deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and AĪ² plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-Ī³ (RorĪ³t)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and AĪ² plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and AĪ² amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.
- Cardiovascular biology,
- Neuroscience
Low-Intensity Pulsed Ultrasound Promotes Oligodendrocyte Maturation and Remyelination by Down-regulating the Interleukin-17A/Notch1 Signaling Pathway in Mice with Ischemic Stroke.
In Research (Washington, D.C.) on 28 April 2025 by Wang, J., Gao, Y., et al.
Increasing evidence indicates that oligodendrocyte (OL) numbers and myelin as a dynamic cellular compartment perform a key role in the maintenance of neuronal function. Inhibiting white matter (WM) demyelination or promoting remyelination has garnered interest for its potential therapeutic strategy against ischemic stroke. Our previous work has shown that low-intensity pulsed ultrasound (LIPUS) could improve stroke recovery. However, it is unclear whether LIPUS can maintain WM integrity early after stroke or promote late WM repair. This study evaluated the efficacy of LIPUS on WM repair and long-term neurologic recovery after stroke. Male adult C57BL/6 mice underwent a focal cerebral ischemia model and were randomized to receive ultrasound stimulation (30 min once daily for 14 days). The effect of LIPUS on sensorimotor function was assessed by modified neurological severity score, rotarod test, grip strength test, and gait analysis up to 28 days after stroke. We found that ischemic stroke-induced WM damage was severe on day 7 and partially recovered on day 28. LIPUS prevented neuronal and oligodendrocyte progenitor cell (OPC) death during the acute phase of stroke (d7), protected WM integrity, and reduced brain atrophy and tissue damage during the recovery phase (d28). To further confirm the effect of LIPUS on remyelination, we assessed the proliferation and differentiation of OPCs. We found that LIPUS did not increase the number of OPCs (PDGFRĪ±+ or NG2+), but markedly increased the number of newly produced mature OLs (APC+) and myelin protein levels. Mechanistically, LIPUS may promote OL maturation and remyelination by down-regulating the interleukin-17A/Notch1 signaling pathway. In summary, LIPUS can protect OLs and neurons early after stroke and promote long-term WM repair and functional recovery. LIPUS will be a viable strategy for the treatment of ischemic stroke in the future. Copyright Ā© 2025 Jingjing Wang etĀ al.
- Cardiovascular biology
Engineering nanoparticles that target fibroblast activation protein in cardiac fibrosis
Preprint on BioRxiv : the Preprint Server for Biology on 26 April 2025 by Maduka, C. V., Rodriguez-Rivera, G. J., et al.
Cardiac fibrosis and dysfunction, hallmarks of debilitating heart disease, are driven by fibroblast activation protein alpha (FAP). The specificity of FAP to the disease creates an opportunity for directed drug delivery, as FAP delineates the fibrotic region. We leverage this vulnerability to target the fibrotic region of the heart, using anti-FAP antibody-modified nanoparticles (NPs) that encapsulate and release the highly specific FAP inhibitor, talabostat. NP crosslinking with an FAP-sensitive peptide attenuates passive release, which is then accelerated in the presence of FAP. Intravenous administration of these NPs results in reversal of established cardiac fibrosis and dysfunction in a rat model of myocardial infarction, using a talabostat dose that is 400,000-fold lower than that used in clinical trials. This innovative and clinically translatable strategy enables targeted drug delivery, overcoming limitations of systemic approaches by reducing therapeutic dose, minimizing off-target effects, and accommodating patient-specific variability in FAP expression.
- Immunology and Microbiology
Lymphotropic Virotherapy Engages DC and High Endothelial Venule Inflammation to Mediate CancerIn SituVaccination
Preprint on MedRxiv : the Preprint Server for Health Sciences on 25 April 2025 by Ludwig, A. L., McKay, Z. P., et al.
Intratumor (IT) inoculation of the rhino:poliovirus chimera, PVSRIPO, yielded objective radiographic responses with long-term survival in 20% of patients with recurrent glioblastoma (rGBM). PVSRIPO infects dendritic cells (DCs) and sets up non-cytopathogenic viral (v)RNA replication, which triggers sustained type-I IFN (IFN-I) signaling and antitumor T cell priming. Here we identify IFN-I signaling in glioma-draining cervical lymph nodes (cLN) as a mediator of polio virotherapy. Transient IFN-I signaling after IT therapy was rescued by cervical perilymphatic injection (CPLI) of PVSRIPO, targeting cLN directly. Dual-site (IT+CPLI) PVSRIPO induced profound inflammatory reprogramming of cLN, enhanced vRNA replication and IFN-I signaling in DCs and High Endothelial Venules (HEV), augmented anti-glioma efficacy in mice, and was associated with T cell activation in rGBM patients. A Ph2 clinical trial of IT+CPLI PVSRIPO is ongoing ( NCT06177964 ). This work implicates the lymphatic system as a novel virotherapy target and demonstrates the CPLI concept to complement brain tumor immunotherapy.
- Immunology and Microbiology
BMAL1 and YAP cooperate to hijack enhancers and promote inflammation in the aged epidermis
Preprint on BioRxiv : the Preprint Server for Biology on 22 April 2025 by Bonjoch, J., SolĆ”, P., et al.
Ageing is characterised by persistent low-grade inflammation that is linked to impaired tissue homeostasis and functionality. However, the molecular mechanisms driving age-associated inflammation remain poorly understood. The mammalian skin is a clinically relevant target of age-driven inflammation associated with compromised barrier function, inefficient wound healing, elevated oxidative stress, and DNA damage accumulation. Here, we show that upon ageing a previously uncharacterised BMAL1-YAP transcriptional complex is hijacked from chromatin regions associated with homeostatic genes in adult epidermis and redirected to inflammation-related enhancers, amplifying the transcription of their target genes. Independently of its known role as a core circadian clock component, BMAL1 partners with the mechanosensitive transcriptional cofactor YAP at enhancer regions to regulate epidermal identity genes. In contrast, in aged skin, BMAL1-YAP complexes bind to enhancers of inflammation-related genes, co-regulated by NF-KB. Interestingly, aged pro-inflammatory signals from the IL-17 pathway activate YAP in a Hippo-independent manner. These findings unveil a transcriptional mechanism underlying epidermal ageing, linking chromatin dynamics to inflammatory transcriptional programs through BMAL1-YAP-bound enhancer rewiring. By elucidating how ageing reprograms transcriptional networks, our work highlights potential strategies to counteract chronic inflammation and restore tissue homeostasis across age-related loss of functionality.
- Homo sapiens (Human)
Suppression of TGF-Ī²/SMAD signaling by an inner nuclear membrane phosphatase complex.
In Nature Communications on 11 April 2025 by Ji, Z., Siu, W. S., et al.
Cytokines of the TGF-Ī² superfamily control essential cell fate decisions via receptor regulated SMAD (R-SMAD) transcription factors. Ligand-induced R-SMAD phosphorylation in the cytosol triggers their activation and nuclear accumulation. We determine how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-Ī² superfamily ligands. We show that R-SMAD dephosphorylation is mediated by an inner nuclear membrane associated complex containing the scaffold protein MAN1 and the CTDNEP1-NEP1R1 phosphatase. Structural prediction, domain mapping and mutagenesis reveals that MAN1 binds independently to the CTDNEP1-NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex causes nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-Ī² ligands. These findings establish CTDNEP1-NEP1R1 as the R-SMAD phosphatase, reveal the mechanistic basis for TGF-Ī² signaling inactivation and highlight how this process is disrupted by disease-associated MAN1 mutations. Ā© 2025. The Author(s).
- Cancer Research,
- Immunology and Microbiology
Ribonuclease 1 Induces T-Cell Dysfunction and Impairs CD8+ T-Cell Cytotoxicity to Benefit Tumor Growth through Hijacking STAT1.
In Advanced Science (Weinheim, Baden-Wurttemberg, Germany) on 1 April 2025 by Yang, W. H., Huang, B. Y., et al.
T-cell-based immunotherapy holds promise for eliminating cancer through T-cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T-cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), which degrades RNA, reduced the expression of effector cytokines and increases immune checkpoint protein levels, inducing T-cell dysfunction. RNase1 expression is positively associated with exhausted T-cell gene signatures and immune checkpoint proteins across several cancer types. Cancer cells expressing RNase1 are resistant to CD8+ T-cell-mediated killing. RNase1 promotes tumor growth in immunocompetent, but not in immunodeficient, mouse models and inhibits CD8+ T-cell activity in vivo. Mechanistically, RNase1 enters T cells and deactivates signal transducer and activator of transcription 1 (STAT1), causing T-cell dysfunction. Loss of RNase1-STAT1 interaction restores CD8+ T-cell cytotoxicity. Notably, a study has found RNase1 might activate CD4+ T cells to inhibit breast cancer growth, while another has indicated it causes immunosuppression in liver cancer. The current research shows that RNase1 does not impact CD4+ T cells in vivo. Overall, the study supports the immunosuppressive role of RNase1 in cancer of negatively regulating STAT1 to impair CD8+ T-cell cytotoxicity. Targeting the RNase1-STAT1 interaction could prevent CD8+ T-cell dysfunction in RNase1-highly expressing cancer patients. Ā© 2025 The Author(s). Advanced Science published by WileyāVCH GmbH.
- Cancer Research
FAP+ cells restrict antibody drug delivery and promote an immunosuppressive environment in head and neck squamous cell carcinoma.
Preprint on Research Square on 25 March 2025 by Grisham, C., Tanaka, H., et al.
Abstract Background Antibody-based therapies (such as anti-EGFR and anti-PD1/L1 agents) have altered the landscape of cancer treatment to improve patient outcomes in formerly unresponsive tumor types. However, this robust response is not ubiquitous for all patients or cancer subtypes. Head and neck squamous cell carcinoma continues to have reduced response in many patient populations regardless of target expression (e.g. EGFR or PDL1). The role of microenvironmental proteins, such as fibroblast activation protein (FAP), may hold the key to improving antibody drug delivery and efficacy. We explore the role of FAP in restricting antibody drug therapies and the subsequent impact of targeting FAP to improve immunotherapy response. Methods Our study uses fluorescently- labeled panitumumab (anti-EGFR) to dissect the impact of FAP on drug delivery in HNSCC patients. Through spatial transcriptomic analysis on these patient samples, we explored the effects of FAP expression on another highly relevant subset of antibody-based drugs- immunotherapy. Based on our patient findings, we used a flank syngeneic mouse model to corroborate the role of FAP in responsive (MOC1) and unresponsive (MOC2) tumor types. Our work culminated in a therapeutic proof-of concept using combination anti-FAP therapy with anti-PDL1. Results Our patient samples revealed that high FAP areas had significantly reduced panitumumab compared to regions with lower FAP expression. Furthermore, depth of penetration within tumor nest was reduced in high FAP areas. Our spatial transcriptomic analysis segmented by FAP, PanCK (tumor), and CD31 (vasculature) showed reduced immunotherapy responsiveness (via TIDE scores) in FAP segments. We confirmed that high-FAP expression was associated with reduced immunotherapy (anti-PDL1) response in our MOC2 tumor-bearing model. We also saw reduced anti-PDL1 drug delivery within MOC2 tumors. However, concurrent administration of an anti-FAP monoclonal antibody improved anti-PDL1 response and overall survival. The administration of anti-FAP agents simultaneously enhanced CD8 T cell infiltration while inducing collagen reorganization (both mechanisms previously linked to improved cancer therapeutic efficacy). Conclusion Our study used human and in vivo data to support a clinically implementable approach for improving antibody-based drug efficacy and response. These findings suggest targeting FAP improves drug penetration and alters the microenvironment to result in higher drug efficacy.
- Biochemistry and Molecular biology,
- Cancer Research,
- Cell Biology,
- Endocrinology and Physiology,
- Immunology and Microbiology
Intrinsic STING of CD8ā+āT cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects.
In Cell Communication and Signaling : CCS on 19 February 2025 by Xu, Q., Hua, X., et al.
Our team has previously found that the stimulator of interferon genes (STING) plays a more significant anti-tumor role in host immune cells than in tumor cells. Although STING is necessary for CD8ā+āT cells to exert immunological activity, its effect on CD8ā+āT cells remains debatable. In this study, we used both in vitro and in vivo models to explore the metabolic effects of STING on CD8ā+āT cells. Peripheral blood lymphocytes were procured from non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 therapy to investigate the correlation between STING expression levels, CD8ā+āT-cell subsets, and immunotherapy efficacy. STING knockout (STING-KO) mice were used for in vivo studies. RNA-seq, seahorse, flow cytometry, electron microscopy, qPCR, immunofluorescence, western blotting, and immunoprecipitation were performed to explore the underlying mechanisms of STING in regulating CD8ā+āT cell function. We discovered that the expression level of STING in immune cells exhibited a significant correlation with immunotherapy efficacy, as well as with the proportion of central memory CD8ā+āT cells. Moreover, we found that the loss of the STING gene results in a reduction in the number of mitochondria and a change in the metabolic pathway selection, thereby inducing excessive glycolysis in CD8ā+āT cells. This excessive glycolysis generates high levels of lactate, which further inhibits IFN-Ī³ secretion and impacts memory T cell differentiation. Correcting the glycolysis disorder partially restored function and IFN-Ī³ secretion, rescued the central memory CD8ā+āT subset, and improved immunotherapy in STING-KO mice. This provides a new treatment strategy for patients with low STING expression and a poor response to immunotherapy. Intrinsic STING of CD8ā+āT cells affects their function through the HK2/Lactate/IFN-Ī³ axis and affects memory differentiation by regulating glycolysis. Ā© 2025. The Author(s).
- Cancer Research
Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer
Preprint on BioRxiv : the Preprint Server for Biology on 4 January 2025 by Elder, A. M., Fairchild, H. R., et al.
Summary Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of immunosuppression. Here we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to Ī±PD-1/Ī±PD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a novel monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody also reduces tumor growth or promotes complete regression of mouse mammary tumors, reduces the immunosuppressive phenotypes in the tumor microenvironment and restores cytotoxic T cells suggesting that SEMA7A may be a candidate for a novel immune-based therapy for breast cancer patients.
- Cancer Research
Breast Cancer Remodels Lymphatics in Sentinel Lymph Nodes
Preprint on BioRxiv : the Preprint Server for Biology on 30 December 2024 by Eichin, D., Takeda, A., et al.
ABSTRACT Cancer metastasis to sentinel lymph nodes (LNs) is often the first marker of potential disease progression. Although it is recognized that tumor-induced lymphangiogenesis facilitates metastasis into LNs in murine models, tumor-induced alterations in human lymphatic vessels remain obscure. We used single-cell RNA sequencing to profile lymphatic endothelial cell (LEC) subsets in paired metastatic and non-metastatic LNs obtained from patients with treatment-naĆÆve breast cancer. Tumor metastasis decreases immunoregulatory LEC subsets, such as PD-L1 + subcapsular sinus LECs, while inducing an increase in capillary-like CD200 + HEY1 + LECs. Matrix Gla protein (MGP) was the most upregulated gene in metastatic LN LECs, and its expression on LECs was TGF-Ī² and VEGF dependent. Upregulated MGP promotes cancer cell adhesion to LN lymphatics. Thus, breast cancer cell metastasis to LNs remodels LEC subsets in human LNs and escalates MGP expression, potentially facilitating cancer cell dissemination through the lymphatic system.
Ly6G+ Neutrophils and Interleukin-17 Are Essential in Protection against Rodent Malaria Caused by Plasmodium berghei ANKA.
In Research (Washington, D.C.) on 20 December 2024 by Su, Z., Li, Q., et al.
Neutrophils are essential in combating invading pathogens such as Plasmodium parasites, but the participation of their subpopulations and mechanisms in resistance to parasite infection are not fully understood. Our study identified a marked increase in Ly6G+ neutrophils in response to P. berghei ANKA infection. Depletion of these cells rendered mice more susceptible to infection. Elevated interleukin-17 (IL-17) levels, which increased the Ly6G+ neutrophil population, were also found to contribute to this protective effect. IL-17 depletion led to reduced neutrophil numbers and increased susceptibility. Furthermore, dihydroartemisinin (DHA) treatment enhanced neutrophil-mediated immune responses through up-regulation of CD18 and CXCR4 factors. These findings revealed key mechanisms of neutrophil and IL-17 interactions in malaria protection and highlighted DHA's potential to promote neutrophil function in combating malaria. Copyright Ā© 2024 Ziwei Su etĀ al.
- Immunology and Microbiology
Pathobiont-induced suppressive immune imprints thwart T cell vaccine responses.
In Nature Communications on 16 December 2024 by Hajam, I. A., Tsai, C. M., et al.
Pathobionts have evolved many strategies to coexist with the host, but how immune evasion mechanisms contribute to the difficulty of developing vaccines against pathobionts is unclear. Meanwhile, Staphylococcus aureus (SA) has resisted human vaccine development to date. Here we show that prior SA exposure induces non-protective CD4+ T cell imprints, leading to the blunting of protective IsdB vaccine responses. Mechanistically, these SA-experienced CD4+ T cells express IL-10, which is further amplified by vaccination and impedes vaccine protection by binding with IL-10RĪ± on CD4+ T cell and inhibit IL-17A production. IL-10 also mediates cross-suppression of IsdB and sdrE multi-antigen vaccine. By contrast, the inefficiency of SA IsdB, IsdA and MntC vaccines can be overcome by co-treatment with adjuvants that promote IL-17A and IFN-Ī³ responses. We thus propose that IL-10 secreting, SA-experienced CD4+ T cell imprints represent a staphylococcal immune escaping mechanism that needs to be taken into consideration for future vaccine development. Ā© 2024. The Author(s).
