Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Innate γδT17 cells play a protective role in DSS-induced colitis via recruitment of Gr-1⁺CD11b⁺ myeloid suppressor cells.

ABSTRACT: Innate γδ T cells play critical roles in mucosal immunity such as regulating intestinal epithelial homeostasis. In addition, γδ T cells are significantly increased in the inflamed mucosa of patients with ulcerative colitis. However, γδ T cells are a heterogeneous population. IL-17-producing versus IFNγ-producing γδ T cells play differential roles in different disease settings. Therefore, dissecting the exact role of different subsets of γδ T cells in colitis is essential for understanding colitis immunopathogenesis. In the current study, we found that TCR δ-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of γδT17 cells but not IFNγ-producing γδ T cells. Immunophenotyping of the cellular infiltrate upon DSS-induced colitis showed a reduced infiltration of Gr-1⁺CD11b⁺ myeloid cells into the sites of inflammation in mice lacking γδT17 cells. Further experiments demonstrated that IL-17, IL-18, and chemokine CXCL5 were critical in Gr-1⁺CD11b⁺ myeloid cell recruitment. In vitro T cell suppressive assay indicated that this Gr-1⁺CD11b⁺ population was immunosuppressive. Depletion of Gr-1⁺CD11b⁺ myeloid cells resulted in an increase severity of DSS-induced colitis. Our study elucidates a new immune pathway involving γδT17-dependent recruitment of Gr-1⁺CD11b⁺ myeloid cells to the site of colitis inflammation important in the protection of colitis initiation and progression.

SUBMITTER: Sun X

PROVIDER: S-EPMC5467993 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SOCS3 Suppression Promoted the Recruitment of CD11b+Gr-1-F4/80-MHCII- Early-Stage Myeloid-Derived Suppressor Cells and Accelerated Interleukin-6-Related Tumor Invasion via Affecting Myeloid Differentiation in Breast Cancer.

Project description:Interleukin-6 (IL-6) is an important trigger for the expansion and recruitment of myeloid-derived suppressor cells (MDSCs), which are regarded to be major coordinators of the immunosuppressive tumor microenvironment. In this study, we constructed IL-6-knockdown breast cancer mice models to explore the molecular events involved in the IL-6-mediated effects on MDSC development. We defined a subset of early-stage MDSCs (e-MDSCs) with the phenotype of CD11b+Gr-1-F4/80-MHCII- in IL-6 high-expressing 4T1 mice mammary carcinoma models, which were the precursors of CD11b+Gr-1+ conventional MDSCs. Furthermore, sustained suppression of SOCS3 and aberrant hyperactivation of the JAK/STAT signaling pathway was exclusively detected in wide-type 4T1 tumor-bearing mice, which promoted the accumulation of e-MDSCs in situ and their immunosuppressive capability in vitro. After blocking the IL-6/STAT3 signaling pathway with the IL-6 receptor antibody or STAT3 antagonist JSI-124 in tumor-bearing mice, significant shrinkage of primary tumors and decrease in lung metastatic nodules were observed in vivo, accompanied by the dramatic decrease of e-MDSC recruitment and recovery of anti-tumor T cell immunity. Thus, SOCS3 suppression accelerated the IL-6-mediated growth and metastasis of mammary carcinoma via affecting myeloid differentiation in breast cancer. Moreover, the IL-6/STAT3 signaling pathway might be a promising candidate target in developing novel therapeutic strategies to eliminate e-MDSCs and improve breast cancer prognosis.

| S-EPMC6064721 | biostudies-literature

Intestinal CD11b+ B Cells Ameliorate Colitis by Secreting Immunoglobulin A.

Project description: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.

| S-EPMC8595478 | biostudies-literature

Gr-1+ CD11b+ myeloid-derived suppressor cells suppress inflammation and promote insulin sensitivity in obesity.

Project description:Activation of immune cells, including macrophages and CD8(+) T cells, contributes significantly to the advancement of obesity and its associated medical complications, such as atherosclerosis, insulin resistance, and type 2 diabetes. However, how the activation of these immune cells is regulated in vivo remains largely unexplored. Here we show that a group of immature myeloid cells with cell surface markers of Gr-1(+) CD11b(+) are highly enriched in peripheral tissues (i.e. liver and adipose tissues) during obesity. Down-regulation of these cells in obese animals significantly increases inflammation and impairs insulin sensitivity and glucose tolerance, whereas elevation of these cells via adoptive transfer has the opposite effects. Mechanistically, we show that under obese conditions, the Gr-1(+) cells suppress proliferation and induce apoptosis of CD8(+) T cells and are capable of skewing differentiation of macrophages into insulin-sensitizing, alternatively activated M2 macrophages. Taken together, our study demonstrates that immature myeloid cells provide a checks-and-balances platform to counter proinflammatory immune cells in the liver and adipose tissue during obesity to prevent overt immune responses.

| S-EPMC3123122 | biostudies-literature

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity.

Project description:Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGF? signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGF? receptor II (T?RII) and are down-regulated in these myeloid cells, leading to increased T?RII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFN?-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGF? and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.

| S-EPMC6031699 | biostudies-literature

NK1.1- CD4+ NKG2D+ T cells suppress DSS-induced colitis in mice through production of TGF-β.

Project description:CD4+ NKG2D+ T cells are associated with tumour, infection and autoimmune diseases. Some CD4+ NKG2D+ T cells secrete IFN-γ and TNF-α to promote inflammation, but others produce TGF-β and FasL to facilitate tumour evasion. Here, murine CD4+ NKG2D+ T cells were further classified into NK1.1- CD4+ NKG2D+ and NK1.1+ CD4+ NKG2D+ subpopulations. The frequency of NK1.1- CD4+ NKG2D+ cells decreased in inflamed colons, whereas more NK1.1+ CD4+ NKG2D+ cells infiltrated into colons of mice with DSS-induced colitis. NK1.1- CD4+ NKG2D+ cells expressed TGF-β and FasL without secreting IFN-γ, IL-21 and IL-17 and displayed no cytotoxicity. The adoptive transfer of NK1.1- CD4+ NKG2D+ cells suppressed DSS-induced colitis largely dependent on TGF-β. NK1.1- CD4+ NKG2D+ cells did not expressed Foxp3, CD223 (LAG-3) and GITR. The subpopulation was distinct from NK1.1+ CD4+ NKG2D+ cells in terms of surface markers and RNA transcription. NK1.1- CD4+ NKG2D+ cells also differed from Th2 or Th17 cells because the former did not express GATA-3 and ROR-γt. Thus, NK1.1- CD4+ NKG2D+ cells exhibited immune regulatory functions, and this T cell subset could be developed to suppress inflammation in clinics.

| S-EPMC5487917 | biostudies-literature

Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner.

Project description:Immunosuppressive CD11b(+) Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or ?-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Con A induced liver damage. Hepatic CD11b(+) Gr-1(+) cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-?-dependent upregulation of CD40 on hepatic CD11b(+) Gr-1(+) cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b(+) Gr-1(+) MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40(-/-) tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.

| S-EPMC4425346 | biostudies-literature

Immunosuppressive role of CD11b+ CD33+ HLA-DR- myeloid-derived suppressor cells-like blast subpopulation in acute myeloid leukemia.

Project description:ObjectiveMyeloid-derived suppressor cells (MDSCs) facilitate tumor growth and development by suppressing T cell function; however, their role in acute myeloid leukemia (AML) remains unclear. Here, we investigated the immunosuppressive role and prognostic value of blasts with an MDSC-like phenotype.MethodsCD11b+ CD33+ HLA-DR- MDSC-like blasts from bone marrow mononuclear cells of patients with AML were analyzed. To investigate their T cell-suppressing function, MDSC-like blasts were isolated using flow cytometry and co-cultured with CD8+ cytotoxic T cells and NB4 leukemic cells. Treatment outcomes were then compared between the MDSC-like blasts low (≤9.76%) and high (>9.76%) groups to identify clinical significance.ResultsMDSC-like blasts showed higher expression of arginase-1 and inducible nitric oxide synthase. Isolated MDSC-like blasts significantly suppressed CD8+ T cell proliferation induced by phytohemagglutinin A. NB4 cell proliferation was significantly suppressed upon co-culture with CD8+ cytotoxic T cells and partially restored upon co-culture with MDSC-like blasts. Patients with high MDSC-like blasts at diagnosis showed substantially shorter overall survival and leukemia-free survival relative to low MDSC-like blasts patients, with subgroup analysis showing statistically significant differences in patients not receiving allogeneic hematopoietic stem cell transplantation.ConclusionWe demonstrated that MDSC-like blasts drive AML-specific immune-escape mechanisms by suppressing T cell proliferation and restoring T cell-suppressed NB4 cell proliferation, with clinically higher fractions of MDSC-like blasts at diagnosis resulting in poor prognosis.

| S-EPMC7541151 | biostudies-literature

Hydrogen sulfide attenuates the recruitment of CD11b⁺Gr-1⁺ myeloid cells and regulates Bax/Bcl-2 signaling in myocardial ischemia injury.

Project description:Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b(+)Gr-1(+) myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b(+)Gr-1(+) myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b(+)Gr-1(+) myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling.

| S-EPMC3998019 | biostudies-other

IFN-? regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1.

Project description:Myeloid derived suppressor cells (MDSCs) play a critical role in suppression of immune responses in cancer and inflammation. Here, we describe how regulation of Bcl2a1 by cytokines controls the suppressor function of CD11b(+) Gr-1(high) granulocytic MDSCs. Coculture of CD11b(+) Gr-1(high) granulocytic MDSCs with antigen-stimulated T cells and simultaneous blockade of IFN-? by the use of anti-IFN-? blocking antibody, IFN-?(-/-) effector T cells, IFN-?R(-/-) MDSCs or STAT1(-/-) MDSCs led to upregulation of Bcl2a1 in CD11b(+) Gr-1(high) cells, improved survival, and enhanced their suppressor function. Molecular studies revealed that GM-CSF released by antigen-stimulated CD8(+) T cells induced Bcl2a1 upregulation, which was repressed in the presence of IFN-? by a direct interaction of phosphorylated STAT-1 with the Bcl2a1 promotor. Bcl2a1 overexpressing granulocytic MDSCs demonstrated prolonged survival and enhanced suppressor function in vitro. Our data suggest that IFN-?/ STAT1-dependent regulation of Bcl2a1 regulates survival and thereby suppressor function of granulocytic MDSCs.

| S-EPMC4140991 | biostudies-literature

CXCL17-derived CD11b+Gr-1+ myeloid-derived suppressor cells contribute to lung metastasis of breast cancer through platelet-derived growth factor-BB.

Project description:BACKGROUND:Metastasis is the major cause of death from breast cancer. Colonization and adaption of metastatic cells in distant organs is a rate-limiting step of the cancer spreading. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood. METHODS:Specific gene contributions to lung metastasis were identified by comparing gene profiles of 4T1 tumors metastasizing to various organs via microarray. The oncogenic properties CXCL17 were examined by in vivo spontaneous metastasis mouse model. The chemotactic activity of CXCL17 on CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) was examined by both in vitro and in vivo models. The therapeutic effects of MDSC depletion and platelet-derived growth factor-BB (PDGF-BB) inhibition were examined by orthotic models. RESULTS:Here, we demonstrate that breast cancer cells secrete CXCL17, which increases the accumulation of CD11b+Gr-1+ MDSCs in the lungs. Metastatic lung-infiltrating CD11b+Gr-1+ MDSCs induce angiogenesis in the lungs and facilitate cancer extravasation and survival that ultimately promote lung metastases. CXCL17 increases CD11b+Gr-1+ MDSCs to express PDGF-BB, which not only contributes to CD11b+Gr-1+ MDSC-mediated angiogenesis in the lung metastatic niche, but is also involved in the colonization of breast cancer. Consequently, both CD11b+Gr-1+ MDSC depletion and PDGF receptor inhibitor effectively prevents CXCL17-driven lung metastasis in breast cancer. More importantly, patients with high levels of CXCL17 have shorter distant metastasis-free and overall survival rates, indicators of poor prognosis. CONCLUSION:Our study reveals that MDSCs derived by CXCL17 contribute to the establishment of a lung metastatic niche by PDGF-BB secretion and provide a rationale for development of CXCL17 or PDGF-BB antagonists to inhibit or prevent lung metastasis in cases of breast cancer.

| S-EPMC6373011 | biostudies-literature