scholarly journals 286.Nuclear factor κB downregulation in human T-cells is essential for the maintenance of the cytokine profile required for pregnancy success

2004 ◽  
Vol 16 (9) ◽  
pp. 286
Author(s):  
S. A. McCracken ◽  
E. D.M. Gallery ◽  
J. M. Morris
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Protein Transport ◽  
Cytokine Profile ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Pregnant Females ◽  
Th 1 ◽  
In Pregnancy

Human pregnancy is associated with a shift away from Th-1 type and a bias towards Th-2 type immune responses. The molecular mechanisms that regulate this are unknown. We assessed the expression and activity of Nuclear Factor (NF)-κB, a transcription factor that plays a central role in regulating immune responses. Nuclear and cytoplasmic fractions were prepared from isolated T-cells from non-pregnant and pregnant females and subjected to Western blotting to assess NF-κB and its' inhibitors IκBα and β expression. NF-κB activity in nuclear extracts was determined by Electrophoretic Mobility Shift Assays. Isolated T-cells were pre-incubated with/without the NF-κB translocation inhibitor SN50 and subsequently stimulated with PMA/ionomycin in the presence of the protein transport inhibitor Brefeldin A. Cytokine production was determined using flow cytometry. Our results demonstrated high levels of immunoreactive NF-κB (p65) in all nuclear fractions of T-cells from non-pregnant females. In contrast, low levels of p65 were detected in nuclear fractions of T-cells from pregnant females. Levels of IκBα and β were also higher in cytoplasmic fractions of T-cells from non-pregnant than from pregnant females. The reduction in p65 levels in pregnancy was consistent with reduced levels of active NF-κB in T-cells from pregnant relative to non-pregnant females. Stimulation of T-cells from non-pregnant females with PMA/ionomycin resulted in IκBα degradation, p65 translocation and subsequent production of Th-1 cytokines IFN-β and IL-2. In contrast, PMA stimulation had no effect on NF-κB activity in T-cells from pregnant females and a reduced effect on IFN-β and IL-2 production. In the presence of SN50, IFN-β and IL-2 production by T-cells from non-pregnant females was attenuated demonstrating a specific role for NF-κB in the production of these Th-1 cytokines. We can therefore conclude that, specific down-regulation of NF-κB in T-cells in pregnancy is an essential requirement for maintaining the cytokine profile necessary for pregnancy success.

scholarly journals Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3+ T reg induction capacity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cytotoxic T Cells ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Adult Bone

Abstract Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

scholarly journals 641 Spatially organized multicellular immune hubs in MMRd and MMRp colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A670-A670
Author(s):  
Jonathan Chen ◽  
Karin Pelka ◽  
Matan Hofree ◽  
Marios Giannakis ◽  
Genevieve Boland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Single Cells ◽  
Large Set ◽  
Colon Tissue

BackgroundImmune responses to cancer are highly variable, with DNA mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. Almost all tumors are infiltrated with immune cells, but the types of immune responses and their effects on tumor growth, metastasis and death, vary greatly between different cancers and individual tumors. Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remains poorly understood.MethodsTo understand the rules governing these varied responses, we transcriptionally profiled 371,223 single cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd treatment-naive patients. We developed a systematic approach to discover cell types, their underlying gene programs, and cellular communities based on single cell RNA-seq (scRNAseq) profiles and applied it to study the distinguishing features of human MMRd and MMRp colorectal cancer. Cellular communities discovered from this analysis were spatially mapped in tissue sections using multiplex RNA in situ hybridization microscopy.ResultsTo understand the basis for differential immune responses in CRC, we first determined and compared the immune cell composition of MMRd and MMRp CRC and normal colon tissue, finding dramatic remodeling between tumor and normal tissue and between MMRd and MMRp tumors, particularly within the myeloid, T cell, and stromal compartments. Among the clusters enriched in MMRd tumors were activated CXCL13+ CD8 T cells. Importantly, gene program co-variation analysis revealed multicellular networks. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated IFNG+ and CXCL13+ T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines (figure 1).ConclusionsOur study provides a rich dataset of cellular states, gene programs and their transformations in tumors across a relatively large cohort of patients with colorectal cancer. Our predictions of several multicellular hubs based on co-variation of gene expression programs, and subsequent spatial localization of two major immune-malignant hubs, organizes a large set of cell states and programs into a smaller number of coordinated networks of cells and processes. Understanding the molecular mechanisms underlying these hubs, and studying their temporal and spatial regulation upon treatment will be critical for advancing cancer therapy.Ethics ApprovalThis study was approved by the DF-HCC institutional review board (protocols 03-189 and 02-240).Abstract 641 Figure 1A coordinated network of CXCL13+ T cells with myeloid and malignant cells expressing ISGs. Image shows a portion of formalin-fixed paraffin-embedded tissue from an MMRd CRC specimen stained with multiplex RNA ISH / IF for PanCK-IF, CD3E-ISH, CXCL10/CXCL11-ISH, CXCL13-ISH, and IFNG-ISH. Note IFNG+ and CXCL13+ cells in proximity to cells expressing the chemokines CXCL10/CXCL11

scholarly journals NFAT control of immune function: New Frontiers for an Abiding Trooper

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 260 ◽  
Author(s):  
Martin Vaeth ◽  
Stefan Feske
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Immune Responses ◽  
Physiological Function ◽  
Large Body ◽  
Immunological Tolerance ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Humoral Immune ◽  
Humoral Immune Responses

Nuclear factor of activated T cells (NFAT) was first described almost three decades ago as a Ca2+/calcineurin-regulated transcription factor in T cells. Since then, a large body of research uncovered the regulation and physiological function of different NFAT homologues in the immune system and many other tissues. In this review, we will discuss novel roles of NFAT in T cells, focusing mainly on its function in humoral immune responses, immunological tolerance, and the regulation of immune metabolism.

scholarly journals IL-12 unmasks latent autoimmune disease in resistant mice.

1996 ◽  
Vol 184 (2) ◽  
pp. 771-775 ◽  
Author(s):  
B M Segal ◽  
E M Shevach
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Immune Responses ◽  
Experimental Allergic Encephalomyelitis ◽  
Basic Protein ◽  
Inbred Mice ◽  
Allergic Encephalomyelitis ◽  
Ifn Gamma ◽  
Th 1 ◽  
Experimental Allergic

Inbred mice exhibit a spectrum of susceptibility to induction of experimental allergic encephalomyelitis (EAE). We have compared the immune responses of the susceptible SJL (H-2s) and resistant B10.S (H-2s) strains to determine factors other than the MHC background which control resistance/susceptibility to EAE. The resistance of the B10.S strain was found to be secondary to an antigen-specific defect in the generation of Th 1 cells that produce IFN gamma. This defect in IFN gamma production could be restored by exposure of the myelin basic protein (MBP)-reactive T cells to IL-12 with the subsequent induction of the ability to transfer EAE to naive recipients. These findings have important implications for the therapeutic use of IL-12 and IL-12 antagonists and may explain the association between relapses/exacerbation of autoimmune disease and infectious diseases.

scholarly journals NF-κB-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy

2007 ◽  
Vol 37 (5) ◽  
pp. 1386-1396 ◽  
Author(s):  
Sharon A. McCracken ◽  
Katrina Hadfield ◽  
Zolaikha Rahimi ◽  
Eileen D. Gallery ◽  
Jonathan M. Morris
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Th1 Immune Responses ◽  
In Pregnancy

scholarly journals Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory and Foxp3+ T regs induction capacity

2020 ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Wide Range ◽  
Adult Bone

Abstract Background: Mesenchymal stem cells (MSCs) display active capacities of suppressing or modulating harmful immune responses through diverse molecular mechanisms. These cells are under extensive translational efforts as cell therapies for immune-mediated diseases and transplantations. A wide range of preclinical studies and limited number of clinical trials using MSCs have not only shown promising safety and efficacy profiles but have also revealed changes in regulatory T cell (T reg) frequency and function. However, the mechanisms underlying this important observation are not well understood. Cell-to-cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes have emerged as possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion. We and others demonstrated that adult bone-marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ (“helper”) and CD8+ (“cytotoxic”) T cells but also indirectly through induction of Tregs. In parallel we demonstrated that fetal liver (FL)-MSCs displays much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs.Methods: MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation and their proliferation potential. Using different in-vitro combinations, we performed co-cultures of FL or BM-MSCs and murine CD3+CD25-T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results: We demonstrated that although both types of MSC exhibit similar phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs.Conclusions: These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

A phase I/II study of telomerase peptide vaccination in combination with chemotherapy in patients with stage IV malignant melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8031-8031 ◽  
Author(s):  
S. Aamdal ◽  
S. Dueland ◽  
O. Engebraaten ◽  
K. Owre ◽  
M. Dyrhaug ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Malignant Melanoma ◽  
Immune Responses ◽  
Phase I ◽  
Treatment Period ◽  
T Cell Response ◽  
Cytokine Profile ◽  
Skin Reactions

8031 Background: A phase I/II feasibility study was conducted to investigate the safety, tolerability and immunological response to vaccination with the telomerase peptide GV1001 (hTERT: 611–626) in combination with temozolomide (T). Methods: Twenty-five patients with malignant melanoma (15 stage M1c,10 stage M1b) received T day 1–5 every four weeks for 1–9 cycles. During the first cycle (4 weeks) they received i.d. injections of 560 μg GV1001 with local GM-CSF in week 2,3 and 4, followed by injections in week 6 and 7 in the second cycle and week 11 in the third cycle. The treatment period was 12 weeks (3 cycles). Booster vaccinations with 560 μg GV1001 were offered every third month. Monitoring of blood samples, clinical examination were performed regularly with radiological staging every 12th week. Immune responses were measured as DTH and in vitro T-cell proliferation. Results: The treatment was generally well tolerated with only grade 1–2 toxicity in most patients. Of 14 patients, 4 developed grade 3 toxicity and one grade 4 toxicity (neutropenia). Immune responses against GV1001 were detected in 17/21 patients (81%) at 12 weeks. Patients receiving up to 9 cycles of T exhibited stable proliferative responses to GV1001 throughout the treatment period. None of the patients had DTH response at trial entry and no DTH responses were observed in patients receiving T. This was not due to a shift in the cytokine profile since cloned GV1001-specific CD4+ T cells displayed a Th1 cytokine profile. Upon evaluation in week 12, 6 patients had SD, 10 PD. One patient had a PR with shrinkage or disappearance of multiple lung metastases. A patient continuing on vaccine alone developed significant DTH response when T therapy was stopped. Conclusions: Telomerase vaccination of patients receiving concomitant T treatment is feasible. The unexpected high proportion of patients showing an immune response indicates that regulatory T-cells may have been removed by T treatment. The chemotherapy may also have influenced effector cells required for development of skin reactions. In spite of lacking DTH response however, the majority of the patients demonstrated significant immune response indicating different regulation of DTH and T-cell response. No significant financial relationships to disclose.

scholarly journals Erythromycin Inhibits Transcriptional Activation of NF-κB, but not NFAT, through Calcineurin-Independent Signaling in T Cells

1999 ◽  
Vol 43 (11) ◽  
pp. 2678-2684 ◽  
Author(s):  
Yosuke Aoki ◽  
Peter N. Kao
Keyword(s):  
T Cells ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Calcium Ionophore ◽  
Inhibitory Effect ◽  
Binding Activity ◽  
Cytokine Gene Expression ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Activated T Cells

ABSTRACT The molecular mechanism of the anti-inflammatory effect of erythromycin (EM) was investigated at the level of transcriptional regulation of cytokine gene expression in T cells. EM (>10−6 M) significantly inhibited interleukin-8 (IL-8) expression but not IL-2 expression from T cells induced with 20 ng of phorbol 12-myristate 13-acetate (PMA) per ml plus 2 μM calcium ionophore (P-I). In electrophoretic mobility shift assays EM at 10−7 to 10−5 M concentrations inhibited nuclear factor kappa B (NF-κB) DNA-binding activities induced by P-I. Reporter gene assays also showed that EM (10−5 M) inhibited IL-8 NF-κB transcription by 37%. The inhibitory effects of EM on transcriptional activation of IL-2 and DNA-binding activity of nuclear factor of activated T cells (NFAT) were not seen in T cells. On the other hand, FK506, which is also a macrolide derivative, inhibited transcriptional activation of both NF-κB and NFAT more strongly than EM did. The mechanism of EM inhibition of transactivation of NF-κB was further investigated in transiently transfected T cells that express calcineurin A and B subunits. Expression of calcineurin did not render transactivation of NF-κB in T cells more resistant to EM, while the inhibitory effect of FK506 on transactivation of NF-κB was attenuated. These findings indicate that EM is capable of inhibiting expression of the IL-8 gene in T cells through transcriptional inhibition and that this inhibition is mediated through a non-calcineurin-dependent signaling event in T lymphocytes.

scholarly journals Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection

2021 ◽  
Author(s):  
Lillian J Juttukonda ◽  
Elisha M Wachman ◽  
Jeffery Boateng ◽  
Mayuri Jain ◽  
Yoel Benarroch ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Nk Cells ◽  
Control Group ◽  
Decidua Basalis ◽  
Tnf Α ◽  
Show Evidence ◽  
Negative Controls ◽  
In Pregnancy

While COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesized that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune resonse is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n=8) or third trimester (3rd Tri COVID, n=8) and SARS-CoV-2-negative controls (Control, n=8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF-α were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-α. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.

scholarly journals Human Fetal Liver MSCs are More Effective Than Adult Bone Marrow MSCs for Their Immunosuppressive, Immunomodulatory and Foxp3+ T regs Induction Capacity

2020 ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Wide Range ◽  
Adult Bone

Abstract Background: Mesenchymal stem cells (MSCs) display active capacities of suppressing or modulating harmful immune responses through diverse molecular mechanisms. These cells are under extensive translational efforts as cell therapies for immune-mediated diseases and transplantations. A wide range of preclinical studies and limited number of clinical trials using MSCs have not only shown promising safety and efficacy profiles but have also revealed changes in regulatory T cell (T reg) frequency and function. However, the mechanisms underlying this important observation are not well understood. Cell-to-cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes have emerged as possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion. We and others demonstrated that adult bone-marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ (“helper”) and CD8+ (“cytotoxic”) T cells but also indirectly through induction of Tregs. In parallel we demonstrated that fetal liver (FL)-MSCs displays much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs.Methods: MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation and their proliferation potential. Using different in-vitro combinations, we performed co-cultures of FL or BM-MSCs and murine CD3+CD25-T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results: We demonstrated that although both types of MSC exhibit similar phenotype profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs.Conclusions: These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

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