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 Intestinal helminth infection transforms the CD4+ T cell composition of the skin

2021 ◽  
Author(s):  
Cajsa H. Classon ◽  
Muzhen Li ◽  
Ada Lerma Clavero ◽  
Junjie Ma ◽  
Xiaogang Feng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Chemokine Receptors ◽  
Immune Cell ◽  
Intestinal Helminth ◽  
Helminth Parasites ◽  
Long Term Effects ◽  
Mesenteric Lymph Nodes ◽  
Cell Composition

AbstractIntestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, implying effects on host immune responses in distal barrier tissues. We herein show that the skin of C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus contain higher numbers of CD4+ T cells compared to the skin of uninfected controls. Accumulated CD4+ T cells were H. polygyrus-specific TH2 cells that skewed the skin CD4+ T cell composition towards a higher TH2/TH1 ratio which persisted after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in the blood and mesenteric lymph nodes draining the infected intestine and was abolished by FTY720 treatment during infection, indicating gut-to-skin trafficking of cells. Remarkably, skin TH2 accumulation was associated with impaired capacity to initiate IFN-γ recall responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel process for T cell colonisation and worm-mediated immunosuppression in this organ.

Association between cetuximab response and differential immunologic gene expression signatures in colorectal cancer metastases.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 558-558 ◽  
Author(s):  
Michael Sangmin Lee ◽  
Benjamin Garrett Vincent ◽  
Autumn Jackson McRee ◽  
Hanna Kelly Sanoff
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Activated T Cells ◽  
Gene Sets

558 Background: Different immune cell infiltrates into colorectal cancer (CRC) tumors are associated with different prognoses. Tumor-associated macrophages contribute to immune evasion and accelerated tumor progression. Conversely, tumor infiltrating lymphocytes at the invasive margin of CRC liver metastases are associated with improved outcomes with chemotherapy. Cetuximab is an IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) and stimulates antibody-dependent cellular cytotoxicity (ADCC) in vitro. However, it is unclear in humans if response to cetuximab is modulated by the immune response. We hypothesized that different immune patterns detected in gene expression profiles of CRC metastases are associated with different responses to cetuximab. Methods: We retrieved gene expression data from biopsies of metastases from 80 refractory CRC patients treated with cetuximab monotherapy (GEO GSE5851). Samples were dichotomized by cetuximab response as having either disease control (DC) or progressive disease (PD). We performed gene set enrichment analysis (GSEA) with GenePattern 3.9.4 using gene sets of immunologic signatures obtained from the Molecular Signatures Database v5.0. Results: Among the 68 patients with response annotated, 25 had DC and 43 had PD. In the PD cohort, 59/1910 immunologic gene sets had false discovery rate (FDR) < 0.1. Notably, multiple gene sets upregulated in monocyte signatures were associated with PD. Also, gene sets consistent with PD1-ligated T cells compared to control activated T cells (FDR = 0.052) or IL4-treated CD4 T cells compared to controls (FDR = 0.087) were associated with PD. Conclusions: Cetuximab-resistant patients tended to have baseline increased expression of gene signatures reflective of monocytic infiltrates, consistent with also having increased expression of the IL4-treated T-cell signature. Cetuximab resistance was also associated with increased expression of the PD1-ligated T cell signature. These preliminary findings support further evaluation of the effect of differential immune infiltrates in prognosis of metastatic CRC treated with cetuximab.

scholarly journals Intestinal helminth infection transforms the CD4+ T cell composition of the skin

2021 ◽  
Author(s):  
Cajsa Helena Classon ◽  
Muzhen Li ◽  
Junjie Ma ◽  
Ada Lerma Clavero ◽  
Xiaogang Feng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Th2 Cells ◽  
Intestinal Helminth ◽  
Long Term Effects ◽  
Cell Composition

Intestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, indicating effects on host immune responses in distal barrier tissues. We herein show that C57BL/6 mice infected with the strictly intestinal nematode Heligmosomoides polygyrus have impaired capacity to initiate skin immune responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. Surprisingly, and in contrast to a previously noted loss of T cells in peripheral lymph nodes, the skin of worm-infected mice harboured higher numbers of CD4+ T cells compared to skin of uninfected controls. H. polygyrus-specific TH2 cells accumulated during infection and remained after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in blood and mesenteric lymph nodes draining intestinal tissues, indicating gut-to-skin trafficking of cells. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel mechanism for T cell colonization and worm-mediated immunosuppression in this organ.

scholarly journals Tumors induce de novo steroid biosynthesis in T cells to evade immunity

2018 ◽  
Author(s):  
Bidesh Mahata ◽  
Jhuma Pramanik ◽  
Louise van der Weyden ◽  
Krzysztof Polanski ◽  
Gozde Kar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
De Novo ◽  
Steroid Biosynthesis ◽  
Genetic Ablation ◽  
Tumor Immunosuppression

ABSTRACTTumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

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.

The in situ local immune response, tumour senescence, and proliferation in colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 412-412
Author(s):  
Campbell SD Roxburgh ◽  
Colin H Richards ◽  
Arfon Powell ◽  
Donald C. Mcmillan ◽  
Joanne E. Edwards ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Cell ◽  
Cancer Survival ◽  
Immune Cell ◽  
Tumour Progression ◽  
Low Grade ◽  
Cd8 Cells ◽  
Immune Cell Infiltrates

412 Background: Immune cell infiltrates play a key role in determining colorectal cancer outcome. It is unclear whether they are tumour or host specific. Increased immunogenicity may relate to senescence or proliferation. Senescence, a state of cell-cycle arrest, slows tumour progression. In animal models, senescence associated regression is mediated by upregulated antitumour immune responses. High proliferation may provoke immune responses. Relationships between senescence, proliferation and immune cell infiltrates have not previously been studied. We explore whether p16ink4a associated senescence relates to T cell infiltrates in colorectal tumours and whether p16ink4a expression, proliferation and T cell infiltrates confer similar survival relationships. Methods: Immunostaining of nuclear p16inka and Ki67 was performed using a tissue microarray. Nuclear p16inkaand Ki67 were scored as high or low expression. (T cell markers CD3/CD45RO/CD8/FOXP3) were scored high/low grade on corresponding full sections (margin/stroma/ cancer cell nest). Results: 230 Stage I-III cancers were studied. High nuclear p16ink4a was expressed in 63% and high proliferation (Ki67 >15% ) in 61%. P16ink4a expression related to reduced margin, stroma and cancer cell nest (CCN) CD45RO cells (P=0.054, P=0.062, P=0.025) and reduced margin CD8 cells (P=0.016). High Ki67 labeling related to increased margin, and CCN CD3 cells (P=0.017, P<0.001), increased margin and CCN CD45RO cells (P=0.023, P<0.001), increased margin, stroma and CCN FOXP3 cells (P<0.001, P=0.001, P<0.001) and increased margin and CCN CD8 cells (P=0.026, P=0.001). On multivariate analysis, TNM stage (P<0.001), low margin CD3 (P=0.014), low margin CD8 (P=0.037), low proliferation (Ki67) (P=0.013) and low senescence (P16ink4a) (P=0.002) conferred poorer cancer survival. Conclusions: p16ink4a expression, proliferation and immune cell infiltrates are independent prognostic factors in colorectal cancer. Proliferation relates to increasing T cell infiltrates but independently influences survival. P16ink4a associated senescence does not appear to mediate improved outcome by upregulating T cell responses. Relationships observed here suggest the opposite.

scholarly journals Immune Checkpoint Blockade with Anti-PD-L1 Prevents Immune Dysfuntion and CLL Development in the TCL1 Adoptive Transfer Mouse Model

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 717-717
Author(s):  
Bola Hanna ◽  
Fabienne McClanahan ◽  
Andrew James Clear ◽  
Shaun Miller ◽  
Peter Lichter ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Adoptive Transfer ◽  
Immune Checkpoint ◽  
Clinical Studies ◽  
Immune Cell ◽  
Immune Dysfunction

Abstract Background: Clinical studies have demonstrated that targeted immunotherapy using PD-1/PD-L1 antibodies induces tumor regression and prolongs disease stabilization in advanced solid cancers. Data on the clinical efficacy in hematological malignancies is largely missing, even though PD-L1/PD-1 interactions have been described as major mediators of immune dysfunction in several leukemias and lymphomas. They are therefore ideal to study if PD-L1/PD-1 blockade has the potential to control disease by restoring anti-tumor immune responses. Several groups showed that chronic lymphocytic leukemia (CLL) provokes immune evasion via PD-L1/PD-1 inhibitory signaling, and that this is very closely mirrored in the Eµ-TCL1 (TCL1) murine model for CLL. Our recent data suggest that in this model, aberrant PD-L1 expression in myeloid cells contributes to the immune defect in CLL. We further demonstrated that the T cell and myeloid cell immune defects in ageing leukemic mice can be induced in young wild-type (WT) mice by adoptive transfer (AT) of murine CLL. In the current study, we used the AT model to test if in vivoPD-L1 blockade corrects leukemia-induced cellular immune dysfunction in myeloid and T cells and enhances anti-tumor immunity. Methods: WT mice transplanted with 4x107 TCL1 splenocytes were randomized to treatment with 10 mg/kg α-murine-PD-L1 (n=15) or isotype antibody (n=10), which was administered i.p. every 3 days starting 1 day after AT, and sacrificed 31 days later. Matched non-transplanted WT mice (n=6) served as additional controls. Immune cell subsets, expression of immune checkpoint markers and T cell effector functions were analyzed by multicolor flow cytometry using cells isolated form spleen, peripheral blood (PB), bone marrow (BM) and peritoneal cavity (PC). Cell proliferation was measured by EdU incorporation in vivo. Immune synapse (IS) formation was assessed by confocal microscopy. Serum cytokines were quantified by multiplex bead arrays. Results: We first confirmed successful engraftment and presence of disease by immunohistochemistry. Compared to isotype controls, α-PD-L1 treated mice had significantly lower spleen weights (median 0.2 g vs 0.9 g, p<0.0001) and a highly significant lower relative frequency of CD19+CD5+ CLL lymphocytes in spleen (1.55% vs 71.69%), PB (10.5% vs 63.53%) and BM (0.26% vs 2.74%) demonstrating very effective tumor control. Compared to non-transplanted animals, α-PD-L1 treated mice showed alterations in almost all phenotypical and functional immune cell parameters, especially in regards to immune cell activation, indicating encounter with and immunological challenge by CLL cells. Along with disease control, α-PD-L1 treated mice had improved immune status as multiple inflammatory cytokines in the serum, including IL-10, TNF-α, CCL2 and GM-CSF were decreased and splenic infiltration of monocytes was reduced. While CLL development skewed monocytes towards Ly6Clow patrolling monocytes, α-PD-L1 treatment restored the presence of Ly6Chi inflammatory monocytes and decreased the expression of adhesion molecules ICAM-1 and PECAM-1. These monocytes regained their differentiation capacity as shown by increased numbers of macrophages and mature MHC-IIhi dendritic cells in the spleens of treated mice. In the T cell compartment, in vivo PD-L1 blockade prevented the CLL-induced CD4/CD8 ratio inversion, the loss of naïve CD8 T cells and the shift towards antigen-experienced and terminally differentiated T cells in spleen, BM and PB. Aberrant expression of immune checkpoint markers PD-1, KLRG-1, LAG-3, and 2B4 was also significantly reduced. The CLL-associated loss of intracellular IL-2 and the increased secretion of IL-4 and IFN-γ in CD4 T cells were prevented in α-PD-L1 treated mice. Respective cytokine patterns were observed in the serum. Functionally, PD-L1 blockade restored CD8 degranulation and IS formation to the level of healthy T cells, and significantly improved both ex vivo and in vivoT cell proliferation. Conclusion: Our in vivodata demonstrate that early PD-L1 blockade very effectively controls CLL development and enables complex effector function of myeloid and T cells, thus restoring anti-tumor immune responses. Targeting PD-L1/PD-1 interactions should therefore be further explored in clinical studies, potentially in combination with novel substances. BH/FM and MS/JGG contributed equally to first and last authorship. Disclosures No relevant conflicts of interest to declare.

scholarly journals The transcriptional repressor HIC1 regulates intestinal immune homeostasis

2016 ◽  
Author(s):  
Kyle Burrows ◽  
Frann Antignano ◽  
Michael Bramhall ◽  
Alistair Chenery ◽  
Sebastian Scheer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vitamin A ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Central Component ◽  
Food Antigens

ABSTRACTThe intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

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.

scholarly journals Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection

2015 ◽  
Vol 112 (29) ◽  
pp. E3883-E3892 ◽  
Author(s):  
Yang Wang ◽  
Huiling Zhong ◽  
Xiaodan Xie ◽  
Crystal Y. Chen ◽  
Dan Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cell Subpopulation ◽  
Tnf Α ◽  
T Cell Immune Responses ◽  
Ifn Γ

Molecular mechanisms for T-cell immune responses modulated by T cell-inhibitory molecules during tuberculosis (TB) infection remain unclear. Here, we show that active human TB infection up-regulates CD244 and CD244 signaling-associated molecules in CD8+ T cells and that blockade of CD244 signaling enhances production of IFN-γ and TNF-α. CD244 expression/signaling in TB correlates with high levels of a long noncoding RNA (lncRNA)-BC050410 [named as lncRNA-AS-GSTT1(1-72) or lncRNA-CD244] in the CD244+CD8+ T-cell subpopulation. CD244 signaling drives lncRNA-CD244 expression via sustaining a permissive chromatin state in the lncRNA-CD244 locus. By recruiting polycomb protein enhancer of zeste homolog 2 (EZH2) to infg/tnfa promoters, lncRNA-CD244 mediates H3K27 trimethylation at infg/tnfa loci toward repressive chromatin states and inhibits IFN-γ/TNF-α expression in CD8+ T cells. Such inhibition can be reversed by knock down of lncRNA-CD244. Interestingly, adoptive transfer of lncRNA-CD244–depressed CD8+ T cells to Mycobacterium tuberculosis (MTB)-infected mice reduced MTB infection and TB pathology compared with lncRNA-CD244–expressed controls. Thus, this work uncovers previously unidentified mechanisms in which T cell-inhibitory signaling and lncRNAs regulate T-cell responses and host defense against TB infection.

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