CCR4 Expression in Hodgkin Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2626-2626
Author(s):  
Lydia Visser ◽  
Myrna van West ◽  
Bea Rutgers ◽  
Sibrand Poppema ◽  
Anke Van Den Berg
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Conflicts Of Interest ◽  
Treg Cells ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Follicular Hyperplasia ◽  
Reactive Lymph Node

Abstract Abstract 2626 In Hodgkin lymphoma (HL) a minority (<1%) of tumor cells is found in a reactive background. The tumor cells shape their environment by the production of several chemokines and cytokines. Production of the chemokine TARC will lead to the attraction of Th2 and Treg cells specifically to involved lymph nodes. Although Treg and Th2 cells are prominent in the infiltrate the expression of its receptor CCR4 is not very high in lymphocytes surrounding the tumor cells. We hypothesized that this is due to internalization of the receptor. We analyzed in which specific compartment of lymphocytes CCR4 is expressed and if CCR4 expression can be recovered when TARC and MDC levels are low. We analyzed 11 lymph node suspensions involved with HL and 11 with follicular hyperplasia (RLN) for expression of CD4, CD26, FoxP3 and CCR4 at t=0 and t=24 hours. We tested the effect of TARC and MDC on CCR4 expression and the mechanism of internalization on normal PBMCs. At t=0 the CD4+ T cell compartment was significantly lower for CD26 in HL (49% vs 68% in RLN, p<0.01) (Table 1). In the comparison between CD26+ and CD26- cells no difference was seen in CCR4 expression in HL but in RLN CCR4 in CD26- cells was significantly lower than in CD26+ cells (p<0.01).Recovery of CCR4 (in average %) after 24 hours was significantly lower in CD26+ cells and FoxP3+ cells in RLN (p<0.01 and p<0.001). Recovery of CCR4 as factor change is significantly higher in HL than in RLN for CCR4 as well as the 3 subpopulations (Table 2). Generally, internalization of CCR4 on lymphocytes is higher with MDC (54 to 90% internalization with 10 and 500ng/ml MDC) than TARC (28 to 48% with 10 and 1000ng/ml TARC) after 2 hours. Internalization occurs through the lipid raft/caveolae dependent pathway as filipin III could inhibit internalization completely and not by clathrin-mediated endocytosis since no effect of inhibition by sucrose was seen. Recovery of CCR4 back on the membrane is fast and by exocytosis since it can be disrupted by exocytosis inhibitor Brefeldin A.Table 1:Percentages subpopulations CD4+ T cells in Hodgkin lymphoma and reactive lymph node by flowcytometry on cell suspensionsHLRLNpCD264968<0.01CCR44137nsFoxP34.41.8nsCCR4/CD26+1925nsCCR4/CD26-2212nsCCR4/FoxP3+5560nsTable 2:Factor of CCR4 recovery after 24 hours in CD4+ subpopulations in Hodgkin lymphoma and reactive lymph node cell suspensionsHLRLNpCCR41.70.9<0.05CCR4 in CD26+1.30.8<0.05CCR4 in CD26-2.91.1<0.05CCR4 in FoxP3+1.60.8<0.05 In conclusion, CD26 expression is significantly lower in HL than RLN. CCR4 expression is equally divided over CD26+ and CD26- cells in HL, but in RLN less is found in CD26-. Recovery of CCR4 expression after culture for 24 hours is lower in RLN than in HL. More CCR4 is recovered in HL especially in the CD26- CD4+ T cell population that is surrounding the tumor cells in HL. Disclosures: No relevant conflicts of interest to declare.

Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma

Blood ◽  
2008 ◽  
Vol 111 (11) ◽  
pp. 5359-5370 ◽  
Author(s):  
Sajjan Mittal ◽  
Neil A. Marshall ◽  
Linda Duncan ◽  
Dominic J. Culligan ◽  
Robert N. Barker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Treg Cells ◽  
Disease Stage ◽  
Serum Lactate Dehydrogenase ◽  
Non Hodgkin Lymphoma

Abstract Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMCs) and involved tissues from 30 patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMCs (median = 20.4% CD4 T cells, n = 20) versus healthy controls (median = 3.2%, n = 13, P < .001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (Rs = 0.79, P < .001). T-cell hyporesponsiveness was reversed by depleting CD25+ cells, or by adding anti–CTLA-4, supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median = 38.8% CD4 T cells, n = 15) versus reactive nodes (median = 11.6%, n = 2, P = .02). When autologous CD25− PBMC fractions were incubated with tumor cells from patients (n = 6) in vitro, there was consistent strong induction and then expansion of cells with the CD4+CD25+FoxP3+ phenotype of classic “natural” Treg cells. This population was confirmed to be suppressive in function. Direct cell-cell interaction of tumor cells with CD25− PBMCs was important in Treg induction, although there was heterogeneity in the mechanisms responsible. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.

Abstract TP460: Regulatory T-Cells and CD4+ T Helper Cell Subsets Are Differentially Regulated and Express Distinct Activation States After Aneurysmal Subarachnoid Hemorrhage (SAH) and During Post-SAH Complications

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Shafqat R Chaudhry ◽  
Sajjad Muhammad
Keyword(s):  
T Cells ◽  
Subarachnoid Hemorrhage ◽  
T Cell ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Helper ◽  
Hla Dr

Background: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications after aneurysm treatment lead to poor clinical outcome. Current research suggests critical role of inflammation during early and delayed brain injury phases over which these complications arise. T helper cells can polarize to multiple functionally unique subsets. Here, we investigate different CD4+ T cell subsets during these brain injury phases after SAH and their dynamics during post-SAH complications. Methods: Anticoagulated peripheral venous blood was obtained from 15 SAH patients on days 1 and 7, and once from healthy controls. After erythrocyte lysis and single cell wash, 1 million cells were stained with different anti-human mouse monoclonal antibodies and were acquired on BD LSR Fortessa. Lymphocytes were gated based on low side scatter and high CD45 expression. Different CD3+CD4+ T cell subsets were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs by CD25 hi and CD127 lo . SAH patients were dichotomized based on presence or absence of different post-SAH complications (hydrocephalus, seizures, CVS, cerebral ischemia) to assess association of T cell subsets with these complications. Results: Total CD4+ T cells were significantly increased after SAH. Interestingly, Th2 cells were significantly decreased and Th17 cells increased on day 7 compared to day 1 after SAH. However, regulatory T-cells were significantly increased on both assessment days compared to controls. The analysis of activation states was done by CD38 and HLA-DR expression. Th1 and Treg cells were significantly increased on day 1 in SAH patients who developed seizures and CVS, respectively. HLA-DR + CD38 + Th2 cells significantly increased on day 1 in SAH patients who developed hydrocephalus, whereas HLA-DR - CD38 - Th1 cells significantly increased on day 1 in patients with infections. HLA-DR - CD38 - Treg cells were significantly reduced on day 1 and day 7 in patients developing cerebral ischemia . Conclusion: CD4+ T cell subsets and Treg cells display dynamic patterns after SAH, and show a distinct pattern of polarization and activation states in specific post-SAH complications.

scholarly journals Regulatory T Cells in Human Cord Blood of Preterm and Term Infants

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2737-2737
Author(s):  
Yuko Hayashi ◽  
Yoshiko Asakura ◽  
Shoko Miura ◽  
Mikiya Endo ◽  
Shoichi Chida ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Preterm Infants ◽  
Cell Population ◽  
Conflicts Of Interest ◽  
Treg Cells ◽  
Cd4 T Cell ◽  
Term Infants ◽  
Term Neonates

Abstract Regulatory T (Treg) cells are a subset of CD4+ T cells that play key roles in the maintenance of immunologic self-tolerance and negative control of immune responses. Treg cells are defined based on expression of CD4, CD25, and transcription factor forkhead box P3 (FoxP3). FoxP3 controls the development and function of Treg cells and can be used as a reliable marker of Treg cells, however, its intracellular localization prohibits its use for the isolation of viable Treg cells. Most FoxP3+ Treg cells express low levels of CD127 in adult peripheral blood, however, the expression of CD127 in cord blood (CB) Treg cells of preterm and term infants at each gestational age remains unknown. Being that CD127 is a cell surface marker, it enables the isolation of viable Treg cells by flow cytometric sorting for further analysis. We analyzed CD4+CD25+FoxP3+ and CD4+CD25+CD127− T cells in preterm and term CB at various gestational ages. CB samples were obtained at Iwate Medical University hospital from preterm and term neonates who had no hereditary disorders, hematologic abnormalities, or immunodeficiency diseases. Of 103 total samples, 36 were obtained from preterm (24–36 gestational weeks) neonates and 67 were obtained from term (37–41 gestational weeks) neonates. Out of 36 preterm infants, 9 were diagnosed with chorioamnionitis histologically. None of the mothers involved in the study had any specific underlying diseases. CB mononuclear cells were isolated and analyzed by FACSCalibur flow cytometer and CellQuestPro software (BD Biosciences). No differences were observed in the proportions of CD25+FoxP3+ (median 4.5%) and CD25+CD127− (median 5.0%) cells in the CD4+ T-cell population. A strong correlation was found between the proportions of CD25+FoxP3+ and CD25+CD127− cells in the CD4+ T-cell population (r=0.96). The proportion of CD25+FoxP3+ cells in the CD4+ T-cell population in the CB of neonates at 24-26, 27-29, and 30-32 gestational weeks was significantly higher than in the CB of neonates at 37-38 and 39-41 gestational weeks. The proportion of CD25+CD127− cells in the CD4+ T-cell population in the CB of neonates at 24-26, 27-29, and 30-32 gestational weeks was also higher than in the CB of neonates at 37-38 and 39-41 gestational weeks. The absolute number of both CD4+CD25+FoxP3+ and CD4+CD25+CD127− T cells did not differ between the CB of preterm and term neonates. Absolute lymphocyte counts in preterm CB were significantly lower than term infants (P<0.05). The proportions of CD25+FoxP3+ and CD25+CD127− cells in the CD4+ T-cell population did not differ between preterm infants with histological chorioamnionitis (n=9) and no histological chorioamnionitis (n=27). We showed that CD127 is preferable to FoxP3 as a marker for identifying Treg cells in CB of various gestational ages and would be useful for separating Treg cells by flow cytometry for therapeutic applications. The proportions of Treg cells in the CB of preterm infants were significantly higher than in the CB of term infants. The high Treg proportion during early gestation suggests that fetal naive T cells have a high propensity to differentiate into Treg cells in response to antigenic stimulation, such as by maternal alloantigens. The functional implications of the high proportion of Treg cells in preterm CB are unknown but may be important for the suppression of undesirable alloimmune reactions to maternal derivatives in utero and the maintenance of tolerance during pregnancy. Disclosures No relevant conflicts of interest to declare.

Enhanced PD‐L1 expression on tumor cells in primary cutaneous large T‐cell lymphoma with CD30 expression as classic Hodgkin lymphoma mimics: A report of lymph node lesions of two cases

2020 ◽  
Vol 70 (10) ◽  
pp. 804-811
Author(s):  
Emiko Takahashi ◽  
Takashi Tsuchida ◽  
Satoshi Baba ◽  
Toyonori Tsuzuki ◽  
Takatoshi Shimauchi ◽  
...  
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Classic Hodgkin Lymphoma

scholarly journals The Roles of Aryl Hydrocarbon Receptor in T Cells at IDO-Positive Tumor Microenvironment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3693-3693
Author(s):  
Soranobu Ninomiya ◽  
Nobuhiko Nakamura ◽  
Junichi Kitagawa ◽  
Takeshi Hara ◽  
Masahito Shimizu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Conflicts Of Interest ◽  
Annexin V ◽  
Activated T Cells ◽  
Raji Cells ◽  
Tryptophan Metabolites

Abstract Introduction:Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor well known to generate biological responses to dioxins. A recent study indicated that kynurenine was an endogenous ligand of AhR and was associated with suppression of the antitumor response. The essential amino acid tryptophan metabolism proceeds via the enzymes IDO, which generates the immunosuppressive metabolites, such as kynurenine. Accumulation of these tryptophan derivatives block antigen-specific T-cell proliferation and induces T-cell death through the AhR. IDO is known to be produced by tumor cells and by some immune cells, such as dendritic cells and macrophages, which reside in tumor-draining lymph nodes or are recruited to tumors. IDO is overexpressed in several human cancers, including prostate, breast, brain, and hematologic malignancies.We previously showed that both IDO expression by tumor cells and high serum kynurenine levels correlate with poor prognosis in non-Hodgkin lymphoma patients. We also revealed that tumor IDO activity can inhibit CD19-specific chimeric antigen-receptor (CAR) T-cells (CARTs) therapy through the action of tryptophan metabolites (Blood. 2015; 125(25): 3905-3916). Therefore, we focused on the AhR in T-cells at IDO-positive tumor microenvironment. Methods and Results:We collected PBMCs from healthy blood donors, and activated the cells with anti-CD3 and anti-CD28 Abs, which mimic physiological T-cell activation. We measured the expression of AhR in activated T-cells using by flow cytometry, and found that the range of expression were from 4.5% to 38%. We then studied the effect of kynurenine on the proliferation of T-cells. The proliferation was assessed by MTS assay. We found that kynurenine significantly inhibited the proliferation of T-cells with high expression of AhR. The percentage inhibition with kynurenine 25µM was 33%. While T-cells with low expression of AhR were not inhibited with even 50µM of kynurenine. To investigate potential mechanisms of T-cell inhibition by kynurenine, we assessed the effect of kynurenine on T-cell apoptosis. We found that kynurenine was also associated with increased the apoptosis of T-cells with high AhR, as assessed by Annexin-V staining (percent Annexin-V positive and 7-AAD negative cells in 0 and 25 µM kynurenine was 11.8% and 36%, respectively). To evaluate the effect of inhibiting AhR in T-cells, we used AhR inhibitor (CH-223191). We found that CH-223191 could blocked the inhibitory effects of kynurenine on T-cells. The percent Annexin-V positive and 7-AAD negative cells in 25 µM kynurenine plus CH-223191 was 22.5%. Next, to assess the functional effects of tryptophan metabolites on the T-cells, we cocultured T-cells (1x106) with GFP-transduced wild-type Raji cells or IDO-transduced Raji cells (1x106). After 72 hours, cells were stained with CD8 antibody to distinguish tumor (GFP+ CD8-) and T-cells (GFP- CD8+). We found that the percentage of T-cells with high AhR in culture with IDO negative and positive Raji cells was 46.7% and 61.4%, respectively, while the percentage of T-cells with low AhR was 41.6% and 39.4%. These data showed that only T-cells with high AhR were inhibited at IDO-positive tumor microenvironment. Next, bone marrow (BM) samples were obtained from multiple myeloma (MM) patients at diagnosis. We could generated the activated T-cells from 10 of 12 BM samples. The expression of AhR in T-cells was ranged from 3.3% to 26.6%. We found that there was a positive correlation between the expression of AhR and the proportion of plasma cells in BM (r=0.76, P=0.04). Discussion:The expression of AhR in activated T cells play an important role in the effect of kynurenine, which is a metabolite produced by IDO. A few clinical trials are evaluating the effects of IDO inhibitors that competitively block the degradation of tryptophan to kynurenine by the enzyme. Because anti-PD-1 and anti-CTLA-4 therapies, which block directly the inhibitory signal in T-cells, have been getting some clinical benefits against such as melanoma and Hodgkin lymphoma. Therefore, AhR in T cells might be a target for IDO-positive hematological malignancies. Disclosures No relevant conflicts of interest to declare.

Age-Related Loss of CD62L Impairs Lymph Node CD4 T Cell Mobilization

2007 ◽  
Vol 1 (1) ◽  
pp. 1-7
Author(s):  
Stephen W. Chensue ◽  
Bo-Chin Chiu ◽  
Valerie R. Stolberg
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Cd4 T Cell ◽  
Age Related ◽  
Cell Mobilization

scholarly journals Lymph node invasion by tumor cells modifies the distribution of dendritic cell subsets and memory T cell profiles in human cancer patients

2014 ◽  
Vol 2 (S3) ◽  
Author(s):  
Nicolás Gonzalo Núñez ◽  
Ana Tereza Nadan ◽  
Louis Pérol ◽  
Maud Milder ◽  
Sophie Viel ◽  
...  
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Dendritic Cell ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Human Cancer ◽  
Memory T Cell ◽  
Dendritic Cell Subsets

scholarly journals Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node

2010 ◽  
Vol 11 (6) ◽  
pp. 520-526 ◽  
Author(s):  
Georgia Perona-Wright ◽  
Katja Mohrs ◽  
Markus Mohrs
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
Helper T Cell ◽  
Reactive Lymph Node

Regulation of IL-17 in chronic inflammation in the human lung

2011 ◽  
Vol 120 (12) ◽  
pp. 515-524 ◽  
Author(s):  
Carol Pridgeon ◽  
Laurence Bugeon ◽  
Louise Donnelly ◽  
Ursula Straschil ◽  
Susan J. Tudhope ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tissue ◽  
Mononuclear Cells ◽  
Human Lung ◽  
Treg Cells ◽  
Orphan Receptor ◽  
Th2 Cells ◽  
Chronic Obstructive ◽  
Interleukin 17

The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4+CD25+) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4+CD25+ T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells) were enriched in the T-cell fraction of lung mononuclear cells. Retrospective stratification of the patient cohort into those with COPD (chronic obstructive pulmonary disease) and non-COPD lung disease revealed no difference in the expression of IL-17 and IL-23 receptor between the groups. We observed that CD4+CD25+ T-cells were present in comparable numbers in COPD and non-COPD lung tissue and with no correlation between the presence of CD4+CD25+ T-cells and IL-17-producing cells. These results suggest that IL-17-expressing cells are present in chronically inflamed lung tissue, but there is no evidence to support this is due to the recruitment or expansion of Treg cells.

scholarly journals Miquelianin Inhibits Allergic Responses in Mice by Suppressing CD4+ T Cell Proliferation

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1120
Author(s):  
Dae Woon Choi ◽  
Sun Young Jung ◽  
Gun-Dong Kim ◽  
So-Young Lee ◽  
Hee Soon Shin
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Reactive Oxygen Species Generation ◽  
Allergic Diseases ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
Heme Oxygenase 1

Allergic diseases, including atopic dermatitis (AD), induce type 2 helper T (Th2) cell-dominant immune responses. Miquelianin (quercetin 3-O-glucuronide, MQL) is an active compound in Rosae multiflorae fructus extract with anti-allergic properties. Here, we investigate the anti-allergic effects of MQL in an ovalbumin (OVA)-induced Th2-dominant mouse model and the associated mechanisms. Oral MQL suppressed cytokine and IL-2 production and proliferation of Th2 cells and upregulated heme oxygenase-1 (HO-1) in splenocytes. Ex vivo MQL suppressed Th1- and Th2-related immune responses by inhibiting CD4+ T cell proliferation, and upregulated HO-1 in CD4+ T cells by activating C-Raf–ERK1/2–Nrf2 pathway via induction of reactive oxygen species generation. In a trimellitic anhydride-induced AD-like mouse model, both topical and oral MQL ameliorated AD symptoms by suppressing Th2 immune responses. Our results suggest that MQL is a potential therapeutic agent for CD4+ T cell-mediated diseases, including allergic diseases.

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