InVivoMAb anti-mouse CXCR3 (CD183)
Product Details
The CXCR3-173 monoclonal antibody reacts with mouse CXCR3 also known as CD183, a 38 kDa chemokine receptor for CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (ITAC). CXCR3 is expressed primarily on activated T cells, NK cells, as well as some epithelial cells and endothelial cells. CXCR3 mediates leukocyte trafficking. Binding of chemokine ligands to CXCR3 induces various cellular responses, including integrin activation, cytoskeletal changes and chemotactic migration. The binding of CXCR3-173 to CXCR3 is reported to inhibit receptor binding of CXCL10 and CXCL11 but not CXCL9.Specifications
| Isotype | Armenian hamster IgG |
|---|---|
| Recommended Isotype Control(s) | InVivoMAb polyclonal Armenian hamster IgG |
| Recommended Dilution Buffer | InVivoPure pH 7.0 Dilution Buffer |
| Conjugation | This product is unconjugated. Conjugation is available via our Antibody Conjugation Services. |
| Immunogen | Peptide consisting of amino acids 1-37 of mouse CXCR3 |
| Reported Applications |
in vivo CXCR3 neutralization Flow cytometry |
| Formulation |
PBS, pH 7.0 Contains no stabilizers or preservatives |
| Endotoxin |
<2EU/mg (<0.002EU/Ī¼g) Determined by LAL gel clotting assay |
| Purity |
>95% Determined by SDS-PAGE |
| Sterility | 0.2 Āµm filtration |
| Production | Purified from cell culture supernatant in an animal-free facility |
| Purification | Protein G |
| RRID | AB_2687730 |
| Molecular Weight | 150 kDa |
| Storage | The antibody solution should be stored at the stock concentration at 4Ā°C. Do not freeze. |
Recommended Products
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Recommended Isotype Control(s)
InVivoMAb polyclonal Armenian hamster IgG
-
Recommended Dilution Buffer
InVivoPure pH 7.0 Dilution Buffer
in vivo CXCR3 neutralization
Jacquelot, N., et al. (2016). "Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma" J Clin Invest 126(3): 921-937. PubMed
Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.
in vivo CXCR3 neutralization, Flow Cytometry
Chaturvedi, V., et al. (2015). "CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage" J Clin Invest 125(4): 1713-1725. PubMed
Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes-induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3-deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications.
in vivo CXCR3 neutralization
Glennie, N. D., et al. (2015). "Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection" J Exp Med 212(9): 1405-1414. PubMed
Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4(+) T cells. These cells produce IFN-gamma and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4(+) TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells.
in vivo CXCR3 neutralization
Yang, H., et al. (2015). "STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells" Cancer Res 75(18): 3812-3822. PubMed
STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3(-/-) cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3(-/-) cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3(Y705F)) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3(-/-) cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3(-/-) and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.
- Mus musculus (House mouse),
- Cancer Research
INHBA/Activin A promotes tumor growth and induces resistance to anti-PD-L1 therapy by suppressing IFN-Ī³ signaling
Preprint on BioRxiv : the Preprint Server for Biology on 8 December 2023 by Li, F., Gu, L., et al.
PubMed
Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, respectively, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. As evidenced by our RNA-Seq and in vitro results, the interferon-Ī³ (IFN-Ī³) signaling pathway was significantly down-regulated by tumor intrinsic activin A. Tumor INHBA deficiency led to lower expression of PD-L1 induced by IFN-Ī³, resulting in poor responsiveness to anti-PD-L1 therapy. On the other hand, decreased secretion of IFN-Ī³-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment. Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy. Our findings reveal that INHBA/activin A is involved in anti-tumor immunity by inhibiting the IFN-Ī³ signaling pathway and considered to be a potential target to overcome anti-PD-L1 resistance in clinical cancer treatment.
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells.
In Nature Communications on 24 November 2023 by Li, S., Li, K., et al.
PubMed
Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8+ T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8+ T cells (CD8+ Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8+ Tpex, the progenitor exhausted CD8+ T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation. Ā© 2023. The Author(s).
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
HDAC3 Inhibition Promotes Antitumor Immunity by Enhancing CXCL10-Mediated Chemotaxis and Recruiting of Immune Cells.
In Cancer Immunology Research on 3 May 2023 by Li, L., Hao, S., et al.
PubMed
It is generally believed that histone deacetylase (HDAC) inhibitors, which represent a new class of anticancer agents, exert their antitumor activity by directly causing cell-cycle arrest and apoptosis of tumor cells. However, in this study, we demonstrated that class I HDAC inhibitors, such as Entinostat and Panobinostat, effectively suppressed tumor growth in immunocompetent but not immunodeficient mice. Further studies with Hdac1, 2, or 3 knockout tumor cells indicated that tumor-specific inactivation of HDAC3 suppressed tumor growth by activating antitumor immunity. Specifically, we found that HDAC3 could directly bind to promotor regions and inhibit the expression of CXCL9, 10, and 11 chemokines. Hdac3-deficient tumor cells expressed high levels of these chemokines, which suppressed tumor growth in immunocompetent mice by recruiting CXCR3+ T cells into the tumor microenvironment (TME). Furthermore, the inverse correlation between HDAC3 and CXCL10 expression in hepatocellular carcinoma tumor tissues also suggested HDAC3 might be involved in antitumor immune regulation and patient survival. Thus, our studies have illustrated that HDAC3 inhibition suppresses tumor growth by enhancing immune cell infiltration into the TME. This antitumor mechanism may be helpful in guiding HDAC3 inhibitor-based treatment. Ā©2023 The Authors; Published by the American Association for Cancer Research.
- Immunology and Microbiology,
- Mus musculus (House mouse)
Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.
In Nature Communications on 12 April 2023 by Onyshchenko, K., Luo, R., et al.
PubMed
Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8+ T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8+ T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8+ T cells increase. Consistent with the surge in tumor-specific CD8+ T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8+ T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers. Ā© 2023. The Author(s).
- FC/FACS,
- Mus musculus (House mouse),
- Immunology and Microbiology
OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic TĀ cell differentiation spectrum.
In Cell Reports Medicine on 21 March 2023 by van der Sluis, T. C., Beyrend, G., et al.
PubMed
Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of TĀ cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ TĀ cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ TĀ cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on TĀ cells to improve cancer immunotherapy. Copyright Ā© 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
- Immunology and Microbiology,
- Neuroscience
Infection induces tissue-resident memory NK cells that safeguard tissue health.
In Immunity on 14 March 2023 by Schuster, I. S., Sng, X. Y. X., et al.
PubMed
Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue residency being cardinal features. A corresponding role for innate cells is unknown. Here, we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived, tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ TĀ cells. Thus, NK cells develop adaptive-like features, including long-term residency in non-lymphoid tissues, to modulate inflammation, restore immune equilibrium, and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases. Copyright Ā© 2023 Elsevier Inc. All rights reserved.
- Immunology and Microbiology,
- Mus musculus (House mouse)
IL9 Polarizes Macrophages to M1 and Induces the Infiltration of Antitumor Immune Cells via MIP-1 and CXCR3 Chemokines.
In Cancer Res Commun on 1 January 2023 by Do-Thi, V. A., Park, S. M., et al.
PubMed
Tumor-associated macrophages (TAM) are involved in tumor progression, metastasis, and immunosuppression. Because TAMs are highly plastic and could alter their phenotypes to proinflammatory M1 in response to environmental stimuli, reeducating TAMs has emerged as a promising approach to overcoming the challenges of solid cancer treatment. This study investigated the effect of IL9 on macrophage M1 polarization and verified its antitumor potential to retrain TAMs and promote chemokine secretion. We demonstrated that IL9 stimulated macrophage proliferation and polarized them toward the proinflammatory M1 phenotype in an IFNĪ³-dependent manner. Tumor-localized IL9 also polarized TAMs toward M1 in vivo and made them release CCL3/4 and CXCL9/10 to recruit antitumor immune cells, including T and natural killer cells, into the tumor microenvironment. Furthermore, peritoneal treatment with recombinant IL9 delayed the growth of macrophage-enriched B16F10 melanoma and 4T1 breast cancer in syngeneic mice, although IL9 treatment did not reduce tumor growth in the absence of macrophage enrichment. These results demonstrate the efficacy of IL9 in macrophage polarization to trigger antitumor immunity. These findings clarified the effect of IL9 on macrophage M1 polarization and verified its antitumor potential through retraining TAMs and chemokine secretion. Ā© 2023 The Authors; Published by the American Association for Cancer Research.
- Mus musculus (House mouse),
- Immunology and Microbiology
Mucosal plasma cells are required to protect the upper airway and brain from infection.
In Immunity on 8 November 2022 by Wellford, S. A., Moseman, A. P., et al.
PubMed
While blood antibodies mediate protective immunity in most organs, whether they protect nasal surfaces in the upper airway is unclear. Using multiple viral infection models in mice, we found that blood-borne antibodies could not defend the olfactory epithelium. Despite high serum antibody titers, pathogens infected nasal turbinates, and neurotropic microbes invaded the brain. Using passive antibody transfers and parabiosis, we identified a restrictive blood-endothelial barrier that excluded circulating antibodies from the olfactory mucosa. Plasma cell depletions demonstrated that plasma cells must reside within olfactory tissue to achieve sterilizing immunity. Antibody blockade and genetically deficient models revealed that this local immunity required CD4+ TĀ cells and CXCR3. Many vaccine adjuvants failed to generate olfactory plasma cells, but mucosal immunizations established humoral protection of the olfactory surface. Our identification of a blood-olfactory barrier and the requirement for tissue-derived antibody has implications for vaccinology, respiratory and CNS pathogen transmission, and B cell fate decisions. Copyright Ā© 2022 Elsevier Inc. All rights reserved.
- Cancer Research
Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis.
In Cell Reports on 11 October 2022 by Poh, A. R., O'Brien, M., et al.
PubMed
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy. Copyright Ā© 2022 The Authors. Published by Elsevier Inc. All rights reserved.
- ELISA,
- Mus musculus (House mouse),
- Cancer Research,
- Cell Biology,
- Immunology and Microbiology
Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.
In Cancer Cell on 10 October 2022 by Chryplewicz, A., Scotton, J., et al.
PubMed
Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 TĀ cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.Copyright Ā© 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
- FC/FACS,
- Mus musculus (House mouse),
- Cancer Research,
- Immunology and Microbiology
Breast cancer cell-derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function.
In The Journal of Clinical Investigation on 3 October 2022 by Wang, J., Wang, Q., et al.
PubMed
Evidence suggests that increased microRNA-155 (miR-155) expression in immune cells enhances antitumor immune responses. However, given the reported association of miR-155 with tumorigenesis in various cancers, a debate is provoked on whether miR-155 is oncogenic or tumor suppressive. We aimed to interrogate the impact of tumor miR-155 expression, particularly that of cancer cell-derived miR-155, on antitumor immunity in breast cancer. We performed bioinformatic analysis of human breast cancer databases, murine experiments, and human specimen examination. We revealed that higher tumor miR-155 levels correlate with a favorable antitumor immune profile and better patient outcomes. Murine experiments demonstrated that miR-155 overexpression in breast cancer cells enhanced T cell influx, delayed tumor growth, and sensitized the tumors to immune checkpoint blockade (ICB) therapy. Mechanistically, miR-155 overexpression in breast cancer cells upregulated their CXCL9/10/11 production, which was mediated by SOCS1 inhibition and increased phosphorylated STAT1 (p-STAT1)/p-STAT3 ratios. We further found that serum miR-155 levels in breast cancer patients correlated with tumor miR-155 levels and tumor immune status. Our findings suggest that high serum and tumor miR-155 levels may be a favorable prognostic marker for breast cancer patients and that therapeutic elevation of miR-155 in breast tumors may improve the efficacy of ICB therapy via remodeling the antitumor immune landscape.
- In Vivo,
- Mus musculus (House mouse),
- Cardiovascular biology,
- Genetics,
- Immunology and Microbiology
Single-Cell RNA sequencing reveals immune cell dynamics and local intercellular communication in acute murine cardiac allograft rejection.
In Theranostics on 29 September 2022 by Chen, Z., Xu, H., et al.
PubMed
Rationale: Transplant rejection is a major impediment to long-term allograft survival, in which the actions of immune cells are of fundamental importance. However, the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection are not completely clear. Methods: Here we performed single-cell RNA sequencing on CD45+ immune cells isolated from cardiac grafts and spleens in a model of murine heterotopic heart transplantation. Moreover, we applied unsupervised clustering, functional enrichment analysis, cell trajectory construction and intercellular communication analysis to explore the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection at single-cell level. The effect of CXCR3 antagonist and neutralizing antibody against its ligand on allograft rejection and T cell function was evaluated in murine heart transplantation model. Results: We presented the immune cell landscape of acute murine cardiac allograft rejection at single-cell resolution, and uncovered the functional characteristics and differentiation trajectory of several alloreactive cell subpopulations, including Mki67hi CTLs, Ccl5hi CTLs, activated Tregs and alloreactive B cells. We demonstrated local intercellular communication and revealed the upregulation of CXCR3 and its ligands in cardiac allografts. Finally, CXCR3 blockade significantly suppressed acute cardiac allograft rejection and inhibited the alloreactive T cell function. Conclusions: These results provide a new insight into the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection, and suggest CXCR3 pathway may serve as a potential therapeutic target for transplant rejection. Ā© The author(s).
- Cancer Research,
- Immunology and Microbiology
IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer.
In Proceedings of the National Academy of Sciences of the United States of America on 2 August 2022 by Ong, L. T., Lee, W. C., et al.
PubMed
Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2+ breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-Ī³ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2+ BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2+, but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2+ BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2+ BC to confer resistance to trastuzumab treatment.
- Cancer Research,
- Immunology and Microbiology
Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy.
In Science Advances on 24 June 2022 by Poh, A. R., Love, C. G., et al.
PubMed
Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically "cold" tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti-programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8+ T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.
- Mus musculus (House mouse),
- Immunology and Microbiology
Maternal-fetal conflict averted by progesterone- induced FOXP3+ regulatory TĀ cells.
In IScience on 17 June 2022 by Severance, A. L., Kinder, J. M., et al.
PubMed
Pregnancy stimulates an intricately coordinated assortment of physiological changes to accommodate growth of the developing fetus, while simultaneously averting rejection of genetically foreign fetal cells and tissues. Despite increasing evidence that expansion of immune-suppressive maternal regulatory TĀ cells enforces fetal tolerance and protects against pregnancy complications, the pregnancy-associated signals driving this essential adaptation remain poorly understood. Here we show that the female reproductive hormone, progesterone, coordinates immune tolerance by stimulating expansion of FOXP3+ regulatory TĀ cells. Conditional loss of the canonical nuclear progesterone receptor in maternal FOXP3+ regulatory TĀ cells blunts their proliferation and accumulation, which is associated with fetal wastage and decidual infiltration of activated CD8+ TĀ cells. Reciprocally, the synthetic progestin 17Ī±-hydroxyprogesterone caproate (17-OHPC) administered to pregnant mice reinforces fetal tolerance and protects against fetal wastage. These immune modulatory effects of progesterone that promote fetal tolerance establish a molecular link between immunological and other physiological adaptions during pregnancy. Ā© 2022 The Author(s).
- Immunology and Microbiology,
- Neuroscience,
- Mus musculus (House mouse)
Secondary influenza challenge triggers resident memory B cell migration and rapid relocation to boost antibody secretion at infected sites.
In Immunity on 12 April 2022 by MacLean, A. J., Richmond, N., et al.
PubMed
Resident memory B (BRM) cells develop and persist in the lungs of influenza-infected mice and humans; however, their contribution to recall responses has not been defined. Here, we used two-photon microscopy to visualize BRM cells within the lungs of influenza -virus immune and reinfected mice. Prior to re-exposure, BRM cells were sparsely scattered throughout the tissue, displaying limited motility. Within 24Ā h of rechallenge, these cells increased their migratory capacity, localized to infected sites, and subsequently differentiated into plasma cells. Alveolar macrophages mediated this process, in part by inducing expression of chemokines CXCL9 and CXCL10 from infiltrating inflammatory cells. This led to the recruitment of chemokine receptor CXCR3-expressing BRM cells to infected regions and increased local antibody concentrations. Our study uncovers spatiotemporal mechanisms that regulate lung BRM cell reactivation and demonstrates their capacity to rapidly deliver antibodies in a highly localized manner to sites of viral replication.Copyright Ā© 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
- Immunology and Microbiology,
- Pathology
The chemokine receptor CXCR3 promotes CD8sup>+/sup> T cell-dependent lung pathology during influenza pathogenesis
Preprint on BioRxiv : the Preprint Server for Biology on 14 February 2022 by Guo, K., Yombo, D. J., et al.
PubMed
h4>ABSTRACT/h4> While the role of CD8 + T cells in influenza clearance is established, their contribution to pathological lung injury is increasingly appreciated. To explore if protective versus pathological functions can be linked to CD8 + T cell subpopulations, we dissected their responses in influenza-infected murine lungs. Our single-cell RNASeq (scRNAseq) analysis revealed significant diversity in CD8 + T cell subpopulations during peak viral load vs. infection-resolved state. While enrichment of Cxcr3 hi CD8 + T effector (T eff ) subset was associated with a more robust cytotoxic response, both CD8 + T eff and CD8 + T central memory (T CM ) exhibited equally potent effector potential. The scRNAseq analysis identified unique regulons regulating the cytotoxic response in CD8 + T cells. The neutralization of CXCR3 mitigated lung injury without affecting viral clearance. IFN-Ī³ was dispensable to regulate the cytotoxic response of Cxcr3 hi CD8 + T cells. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury. h4>TEASER/h4> The CXCR3 expressing CD8+ T cell subset causes severe lung pathology and exacerbates disease severity without affecting viral clearance during influenza infection
- Immunology and Microbiology,
- Pathology
Mycobacterial infection aggravates Helicobacter pylori-induced gastric preneoplastic pathology by redirection of de novo induced Treg cells.
In Cell Reports on 8 February 2022 by Artola-BorƔn, M., Fallegger, A., et al.
PubMed
The two human pathogens Helicobacter pylori and Mycobacterium tuberculosis (Mtb) co-exist in many geographical areas of the world. Here, using a co-infection model ofĀ H.Ā pyloriĀ and the Mtb relativeĀ M.Ā bovisĀ bacillus Calmette-GuĆ©rin (BCG), we show that both bacteria affect the colonization and immune control of the respective other pathogen. Co-occurring M.Ā bovis boosts gastric Th1 responses and H.Ā pylori control and aggravates gastric immunopathology. H.Ā pylori in the stomach compromises immune control of M.Ā bovis in the liver and spleen. Prior antibiotic H.Ā pylori eradication or M.Ā bovis-specific immunization reverses the effects of H.Ā pylori. Mechanistically, the mutual effects can be attributed to the redirection of regulatory TĀ cells (Treg cells) to sites of M.Ā bovis infection. Reversal of Treg cell redirection by CXCR3 blockade restores M.Ā bovis control. In conclusion, the simultaneous presence of both pathogens exacerbates the problems associated with each individual infection alone and should possibly be factored into treatment decisions. Copyright Ā© 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
- In Vitro,
- Mus musculus (House mouse),
- Immunology and Microbiology
CXCR3 regulates stem and proliferative CD8+ T cells during chronic infection by promoting interactions with DCs in splenic bridging channels.
In Cell Reports on 18 January 2022 by Bangs, D. J., Tsitsiklis, A., et al.
PubMed
Production of effector CD8+ TĀ cells during persistent infection requires a stable pool of stem-like cells that can give rise to effector cells via a proliferative intermediate population. In infection models marked by TĀ cell exhaustion, this process can be transiently induced by checkpoint blockade but occurs spontaneously in mice chronically infected with the protozoan intracellular parasite Toxoplasma gondii. We observe distinct locations for parasite-specific TĀ cell subsets, implying a link between differentiation and anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on TĀ cells does not prevent white pulp-to-red pulp migration but reduces interactions with CXCR3 ligand-producing dendritic cells (DCs) and impairs memory-to-intermediate transition, leading to a buildup of memory TĀ cells in the red pulp. Thus, CXCR3 increases TĀ cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic mechanism for modulating effector differentiation in response to environmental signals.Copyright Ā© 2022 The Authors. Published by Elsevier Inc. All rights reserved.
- In Vivo,
- Mus musculus (House mouse),
- Immunology and Microbiology,
- Neuroscience
Expeditious recruitment of circulating memory CD8 TĀ cells to the liver facilitates control of malaria.
In Cell Reports on 2 November 2021 by Lefebvre, M. N., Surette, F. A., et al.
PubMed
Circulating memory CD8 TĀ cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 TĀ cells (Tem) infiltrate the liver within 6Ā hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 TĀ cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory "sensing-and-alarm" function and ā¼42Ā hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections.Copyright Ā© 2021 The Author(s). Published by Elsevier Inc. All rights reserved.