Reciprocal role of hBD2 and hBD3 on the adaptive immune response by measuring T lymphocyte proliferation in terms of CD4 and CCR6 expression

2018 ◽  
Vol 35 (3) ◽  
Author(s):  
Nima Taefehshokr ◽  
Alireza Isazadeh ◽  
Amin Oveisi ◽  
Yashar Azari Key ◽  
Sina Taefehshokr
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Adaptive Immune Response ◽  
T Cell Proliferation ◽  
Peripheral Blood Mononuclear ◽  
Adaptive Immune ◽  
T Lymphocyte Proliferation

Abstract Background Human β-defensins (hBD2 and hBD3) are small cationic antimicrobial peptides of innate immune system which can act as a barrier against the majority of pathogens, contributing to the host immune defence. Objective The aim of study is to determine whether hBD2 and hBD3 play a role in development and proliferation of human effector CD4 T cells or not. Furthermore, if enhanced proliferation is observed in the presence of hBD2 and hBD3, these data will demonstrate whether chemokine receptor type 6 (CCR6) is required to be present for this activity to occur. Methods In this study, we examined the effect of hBD2 and hBD3 on CD4+ T cell proliferation in CCR6+ and CCR6− T cells through co-culture of peripheral blood mononuclear cells with anti-CD3 and anti-CD28 stimulation in the presence or absence of hBD2 and hBD3. Proliferation was assessed using flow cytometry. Results It was demonstrated that, co-culture with hBD2 and hBD3 led to up-regulation of CD4+ T cell proliferation after 72 h whereas, CD4+ T cell proliferation was suppressed after 96 h. On the other hand, CCR6− and CCR6+ T cell proliferation was up-regulated after 72 h. But, CCR6+ only was down-regulated in the second cycle in the presence of hBD3. In contrast, after 96 h CCR6+ and CCR6− T cell proliferation was decreased. Conclusion Collectively, our data indicated that hBD2 and hBD3 play a positive and negative regulatory role in development and proliferation of human effector CD4+ T cells which is essential for optimal adaptive immune responses and the control of immunopathology.

CD11b+gr-1+ myeloid Derived Suppressor Cells (MDSC) In Normal Bone Marrow Suppress T Cell Proliferation and Enhance T-Regulatory Function Via a IL10-, IL4- and IDO-Independent Mechanism

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4801-4801 ◽  
Author(s):  
Parvin Forghani ◽  
Wayne Harris ◽  
jian-Ming Li ◽  
M.R. Khorramizadeh ◽  
Edmund Waller
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulatory Function ◽  
T Cell Proliferation ◽  
Suppressive Activity ◽  
Ifn Γ

Abstract Abstract 4801 MDSC have been described as an important negative regulators of autologous anti-cancer immune responses. Considering the important role of MDSC in immune regulation in allogenic stem cell and organ transplantation, we undertook an investigation of the mechanism(s) by which MDSC inhibit T–cell activation and proliferation, and tested the hypothesis that local cytokine secretion or IDO activity is required for suppression of T-cell proliferation. Two separate populations CD11bhiGr-1hi and CD11bhi Gr-1int were isolated by high-speed FACS from lineage- BM antigen presenting cells (C57 & BALB/c mice). Both MDSC subsets had potent capacity for in–vitro suppression of CD4+ and CD8+ T cells proliferation in response to anti-CD3/anti-CD28 beads and Con A. A ratio of 0.5/1 MDSC: T-cells were sufficient to inhibit >66% control levels of T-cell proliferation. MDSC isolated from transgenic mice that had been “knocked-out” for IFN-γ and IDO had equivalent suppressive activity as MDSC from wild-type donors. Addition of saturating concentrations of anti IL-10 and IL-4 MAb, or in combination with anti- IFN-γ MAb did not abrogate MDSC-suppressive activity. Ex-vivo culture of MDSC with mitogen-activated T-cells generated two—fold more Fox-p3 T-reg compared with cultures of T cell plus mitogen. Data will be presented regarding the novel role of MDSC involving in the homeostasis regulation of normal T-cell activation and proliferation in non-tumor-bearing mice. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lactobacillus paracasei subsp. paracasei B21060 Suppresses Human T-Cell Proliferation

2007 ◽  
Vol 75 (4) ◽  
pp. 1730-1737 ◽  
Author(s):  
Ilaria Peluso ◽  
Daniele Fina ◽  
Roberta Caruso ◽  
Carmine Stolfi ◽  
Flavio Caprioli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Intracellular Ph ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Lactobacillus Paracasei ◽  
T Cell Proliferation ◽  
T Cell Growth

ABSTRACT Recent studies have shown that probiotics are beneficial in T-cell-mediated inflammatory diseases. The molecular mechanism by which probiotics work remains elusive, but accumulating evidence indicates that probiotics can modulate immune cell responses. Since T cells express receptors for bacterial products or components, we examined whether different strains of lactobacilli directly regulate the functions of human T cells. CD4+ T cells were isolated from blood and intestinal lamina propria (LP) of normal individuals and patients with inflammatory bowel disease (IBD). Mononuclear cells were also isolated from Peyer's patches. Cells were activated with anti-CD3/CD2/CD28 in the presence or absence of Lactobacillus paracasei subsp. paracasei B21060, L. paracasei subsp. paracasei F19, or L. casei subsp. casei DG. Cell proliferation and death, Foxp3, intracellular pH, and cytokine production were evaluated by flow cytometry. We showed that L. paracasei subsp. paracasei B21060 but neither L. paracasei subsp. paracasei F19 nor L. casei subsp. casei DG inhibited blood CD4+ T-cell growth. This effect was associated with no change in cell survival, expression of Foxp3, or production of gamma interferon, interleukin-4 (IL-4), IL-5, and IL-10. L. paracasei subsp. paracasei B21060-mediated blockade of CD4+ T-cell proliferation required a viable bacterium and was associated with decreased MCT-1 expression and low intracellular pH. L. paracasei subsp. paracasei B21060 also inhibited the growth of Peyer's patch mononuclear cells, normal lymphocytes, and IBD CD4+ LP lymphocytes without affecting cytokine production. The data show that L. paracasei subsp. paracasei B21060 blocks T-cell growth, thus suggesting a mechanism by which these probiotics could interfere with T-cell-driven immune responses.

scholarly journals Caspase Inhibitors Attenuate Superantigen-Induced Inflammatory Cytokines, Chemokines, and T-Cell Proliferation

2004 ◽  
Vol 11 (3) ◽  
pp. 621-624 ◽  
Author(s):  
Teresa Krakauer
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Therapeutic Modality ◽  
T Cell Proliferation ◽  
Toxic Shock ◽  
Peripheral Blood Mononuclear ◽  
Caspase Inhibitors ◽  
Cytokines And Chemokines

ABSTRACT Proinflammatory cytokines mediate the toxic effect of superantigenic staphylococcal exotoxins (SE). A pan-caspase inhibitor suppressed SE-stimulated T-cell proliferation and the production of cytokines and chemokines by human peripheral blood mononuclear cells. These data suggest that caspase inhibitors may represent a novel therapeutic modality for treating SE-induced toxic shock.

Microrna-17-92 Cluster: Novel Target for Controlling Gvhd While Preserving GVL Effect

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 845-845
Author(s):  
Yongxia Wu ◽  
David Bastian ◽  
Jessica Lauren Heinrichs ◽  
Jianing Fu ◽  
Hung Nguyen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cd8 T Cells ◽  
Locked Nucleic Acid ◽  
T Cell Proliferation ◽  
Allogeneic Bone

Abstract Graft-versus-host disease (GVHD) remains a life threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). Donor T cells are the key pathogenic effectors in the induction of GVHD. MicroRNAs (miRs) have been shown to play an important role in orchestrating immune response, among which miR-17-92 cluster is one of the best characterized miR clusters that encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1 and 92-1. Although regulatory functions of miR-17-92 cluster have been elaborated in a variety of immune responses including anti-infection, anti-tumor, and autoimmunity, the role of this miR cluster in the modulation of T-cell response to alloantigens and the development of GVHD has not been explored previously. Based on the previous report that miR-17-92 promotes Th1 responses and inhibits induced regulatory T-cell (iTreg) differentiation in vitro, we hypothesized that blockade of miR-17-92 would constrain T-cell alloresponse and attenuate GVHD. To evaluate the function of miR-17-92 on T-cell alloresponse, we utilized the mice with miR-17-92 conditional knock-out (KO) on T cells as donors, and compared the alloresponse of WT and KO T cells after allogeneic bone marrow transplantation (allo-BMT). We observed that KO T cells had substantially reduced ability to proliferate and produce IFNγ as compared to WT counterparts 4 days after cell transfer. Interestingly, CD4 but not CD8 KO T cells had increased cell death in the population of fast-dividing T cells. Thus, miR-17-92 cluster promotes activation and expansion of both CD4 and CD8 T cells, and inhibits activation-induced cell death of CD4 but not CD8 T cells at the early stage of alloresponse in vivo. We further evaluated the role of miR-17-92 on T cells in the development of acute GVHD in a fully MHC-mismatched BMT model. In sharp contrast to WT T cells that caused severe GVHD and resulted in 100% mortality of the recipients, KO T cells were impaired in causing severe GVHD reflected by mild clinical manifestations and no mortality. These observations were extended to MHC-matched but minor antigen-mismatched as well as haploidentical BMT models that are more clinically relevant. We next addressed the critical question whether T cells deficient for miR-17-92 are still capable of mediating graft-versus-leukemia (GVL) effect. Using A20 lymphoma and P815 mastocytoma cell lines, we demonstrated that the KO T cells essentially retained the GVL activity in MHC-mismatched and haploidentical BMT model, respectively. Mechanistic studies revealed that miR-17-92 promoted CD4 T-cell proliferation, survival, migration to target organs, and Th1-differentiation, but reduced Th2-differentiation and iTreg generation. However, miR-17-92 had less impact on CD8 T-cell proliferation, survival, IFNγ production, and cytolytic activity reflected by granzyme B and CD107a expression. Moreover, miR-17-92 negatively regulated TNFα production by both CD4 and CD8 T cells. We therefore conclude that miR-17-92 cluster is required for T cells to induce severe GVHD, but it is dispensable for T cells to mediate the GVL effect. To increase translational potential of our findings, we designed the locked nucleic acid (LNA) antagomirs specific for miR-17 or miR-19, which have been reported to be the key members in this cluster. We observed that the treatment with anti-miR-17 significantly inhibited T-cell expansion and IFNγ production in response to alloantigen in vivo, and anti-miR-19 was more effective. Furthermore, our ongoing experiment showed the treatment with anti-miR-17 or anti-miR-19 was able to considerably attenuate the severity of GVHD as compared to scrambled antagomir in a MHC-mismatched BMT model. Taken together, the current work reveals that miR-17-92 cluster is essential for T-cell alloresponse and GVHD development, and validates miR-17-92 cluster as promising therapeutic target for the control of GVHD while preserving GVL activity in allogeneic HCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon γ production

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2899-2907 ◽  
Author(s):  
Duncan Howie ◽  
Susumo Okamoto ◽  
Svend Rietdijk ◽  
Kareem Clarke ◽  
Ninghai Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Dna Synthesis ◽  
Interferon Γ ◽  
T Cell Proliferation ◽  
Wild Type ◽  
Ifn Γ

CD150 (signaling lymphocyte activation molecule [SLAM]) is a self-ligand cell surface glycoprotein expressed on T cells, B cells, macrophages, and dendritic cells. To further explore the role of CD150 signaling in costimulation and TH1 priming we have generated a panel of rat antimouse CD150 monoclonal antibodies. CD150 cell surface expression is up-regulated with rapid kinetics in activated T cells and lipopolysaccharide/interferon γ (IFN-γ)–activated macrophages. Anti-CD150 triggering induces strong costimulation of T cells triggered through CD3. DNA synthesis of murine T cells induced by anti-CD150 is not dependent on SLAM-associated protein (SAP, SH2D1A), because anti-CD150 induces similar levels of DNA synthesis in SAP−/− T cells. Antibodies to CD150 also enhance IFN-γ production both in wild-type and SAP−/− T cells during primary stimulation. The level of IFN-γ production is higher in SAP−/− T cells than in wild-type T cells. Anti-CD150 antibodies also synergize with interleukin 12 (IL-12) treatment in up-regulation of IL-12 receptor β2 mRNA during TH1 priming, and inhibit primary TH2 polarization in an IFN-γ–dependent fashion. Cross-linking CD150 on CD4 T cells induces rapid serine phosphorylation of Akt/PKB. We speculate that this is an important pathway contributing to CD150-mediated T-cell proliferation.

scholarly journals Role of Interleukin 12 and Costimulators in T Cell Anergy In Vivo

1997 ◽  
Vol 186 (7) ◽  
pp. 1119-1128 ◽  
Author(s):  
Luk Van Parijs ◽  
Victor L. Perez ◽  
Andre Biuckians ◽  
Robert G. Maki ◽  
Cheryl A. London ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Proliferation ◽  
Interleukin 12 ◽  
Potent Inducer ◽  
T Cell Anergy ◽  
Cell Anergy

The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti–CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti–CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one.

scholarly journals Activation of GABA(A) receptors inhibits T cell proliferation

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251632
Author(s):  
Emma L. Sparrow ◽  
Sonya James ◽  
Khiyam Hussain ◽  
Stephen A. Beers ◽  
Mark S. Cragg ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mononuclear Cells ◽  
Cell Activity ◽  
Translocator Protein ◽  
T Cell Proliferation ◽  
Mouse Splenocytes ◽  
Gaba A ◽  
Human T Cell

Background The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity. Methods Mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed. Results Positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation. Conclusions We conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.

Pre-Transplant CSF-1 Therapy Expands the Recipient Macrophage Pool and Modulates Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 242-242
Author(s):  
Daigo Hashimoto ◽  
Andrew Chow ◽  
Melanie Greter ◽  
Marylene Leboeuf ◽  
Florent Ginhoux ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Low Dose ◽  
T Cell Proliferation ◽  
Lymphoid Tissues ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Abstract 242 Host antigen presenting cells are critical to activate allo-reactive T cells and to initiate acute graft versus host disease (GVHD) after allogeneic bone marrow transplantation (BMT). However, while the role of host dendritic cells (DCs) in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. In this study we revisited the role of host macrophages in GVHD. To this end we used an anti-CSF-1R monoclonal antibody (aCSF1R) to reduce macrophages but not DC numbers in lymphoid organs. We treated recipient C57BL/6 mice with αCSF1R on days -5 to -3 followed on day 0 by TBI and i.v. injection of BM cells and splenocytes isolated from MHC-mismatched BALB/c donor. We found that host macrophages that persist in the spleen and LN of recipient mice were severely reduced by αCSF1R, whereas host DCs remained unaffected by the treatment. We also found that αCSF1R-treatement significantly enhanced GVHD morbidity and mortality (Figure left panel) after allogeneic BMT, enhanced donor T cell expansion in recipient spleen, LN and liver, and increased IFN-gamma and TNF-alfa sera levels compared to mice treated with control IgG. Similar results were obtained when low dose Lip-Clod was administered 10 days prior to transplant in order to deplete macrophages in lymphoid tissues but not host DC whose half-life in lymphoid tissues does not exceed three days allowing them to recover to normal at the time of transplant. Our results revealed that in contrast to a previous report in which higher Lip-Clod doses administered 7 and 2 days prior to transplant led to the depletion of both DCs and macrophages and improved GVHD, low dose Lip-Clod administered 10 days prior to transplant, depleted host macrophages but not DCs and aggravated GVHD. We also explored the mechanisms by which host macrophages could potentially control donor T cell expansion induced by host DC after allo-HCT. We found that host macrophages isolated from allogeneic recipients inhibited the proliferation of allo-reactive T cells co-cultured with host C57BL/6 DC partly through a cell-cell contact pathway. Host macrophages were also able to engulf and reduce alloreactive T cells after few hrs of culture. Consistently, 18 hrs after allo-HCT, the number of donor T cells accumulating in the recipient spleen and mesenteric LNs were higher in Ab-treated mice compared to the control groups and CFSE-labeled donor T cells were engulfed by splenic macrophages during the first day of transplant and prior to the initiation of donor T cell proliferation. These results suggest that host macrophages limit the expansion of donor T cells through their ability to engulf donor T cell and to inhibit donor T cell proliferation induced by host DC stimulation. Further supporting the importance of host macrophages in regulating the development of GVHD, we found that pre-transplant administration of the cytokine CSF-1 increased the number of spleen macrophages, limited the expansion of donor allo-reactive T cells and improved GVHD outcome (Figure right panel). Altogether, we showed that in contrast to host DCs, host macrophages modulate GVHD through their ability to limit donor T cell activation and expansion. In addition, our data also identify pre-transplant CSF-1 injection as a novel clinical strategy for the prevention of GVHD in patient candidate for allo-HCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction

2020 ◽  
Vol 22 (7) ◽  
pp. 967-978 ◽  
Author(s):  
Benjamin T Himes ◽  
Timothy E Peterson ◽  
Tristan de Mooij ◽  
Luz M Cumba Garcia ◽  
Mi-Yeon Jung ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Extracellular Vesicles ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Cell Inhibition

Abstract Background Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role of EV-associated PD-L1 in the formation of immunosuppressive monocytes. Methods Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T-cell proliferation. PD-L1 constitutive overexpression or short hairpin RNA–mediated knockdown was used to determined the role of altered PD-L1 expression. Results GBM EVs interact with both T cells and monocytes but do not directly inhibit T-cell activation. However, GBM EVs induce immunosuppressive monocytes, including myeloid-derived suppressor cells (MDSCs) and nonclassical monocytes (NCMs). MDSCs and NCMs inhibit T-cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes T-cell inhibition. Conclusion These findings indicate that GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T-cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.

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