Characterization Of T Follicular Helper Cells In Patients With Low Risk Myelodysplastic Syndromes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4729-4729
Author(s):  
Polyxeni Lampropoulou ◽  
Evgenia Verigou ◽  
Argiris Symeonidis ◽  
Charalambos Gogos ◽  
Elena E. Solomou
Keyword(s):  
Transcription Factor ◽  
Myelodysplastic Syndromes ◽  
T Helper Cells ◽  
Low Risk ◽  
T Helper ◽  
Cd4 Cells ◽  
Tfh Cells ◽  
Control Subjects ◽  
Helper Cells ◽  
Follicular Helper

A subpopulation of CD4+helper T cells, T-follicular helper cells (TFH), are characterized by the surface expression of CXCR5, ICOS, and PD1, the transcription factor Bcl-6, and produce mainly IL-21, but also IL-17, IL-4, and IFN-γ. They represent the major population that helps B cells to turn into plasma cells and they are implicated in the pathogenesis of different autoimmune diseases. Peripheral CXCR5+CD4+ T helper cells (p-TFH) are the circulating component of TFH. p-TFH cells have been extensively studied in the context of inflammation and autoimmunity. Patients with systemic lupus erythematosus and rheumatoid arthritis have increased p-TFH. Immune dysregulation characterizes low risk myelodysplastic syndromes (MDS). The expression of p-TFH in patients in low risk MDS has not been previously evaluated. To examine the expression of p-TFH in this disease we isolated peripheral blood mononuclear cells (PBMCs) from patients with low risk MDS (n=20, Refractory Anemia,RA; and Refractory Cytopenias with Multilineage Dysplasia, RCMD) and ten healthy, age- matched controls. Written informed consent was obtained from all study subjects. PBMCs were left untreated or activated with PMA and Ionomycin, in the presence of Brefeldin A, for 5 hours. Subsequently, cells were stained with the surface markers CXCR5, CD4, CD45RO, ICOS and intracellular IL-21, and analyzed by flow cytometry. Patients with MDS show decreased CD4+ICOS+ cells compared to healthy controls (5,34±1,44% vs 8,69±4,08% respectively, p=0.028). The median percentages of CXCR5+CD4+ cells (estimated on CD4+ cells) before stimulation were lower in MDS patients although not statistically significant different from the control subjects. The expansion of the CXCR5+CD4+ population after stimulation was higher in MDS patients compared to healthy individuals (ratio of stimulated to unstimulated CXCR5+CD4+ cells of MDS patients: 1.44±0.47 vs control: 1.23± 0.32, p=0.027). MDS patients at diagnosis showed increased median levels of IL-21 producing CXCR5+CD4+ cells compared to patients previously treated with erythropoietin (EPO), (21,34±10,14% vs 17,55±12,91, respectively). Additionally, patients with RA showed increased CXCR5+CD4+IL-21+ cells compared to the RCMD patients (22,39±11,76% vs 17,84±10,70%, respectively). Collectively, the percentage of IL-21 producing CXCR5+CD4+ cells did not differ significantly between the MDS and control groups (20,57± 10,12% vs 19,86± 11,03%, respectively). The presence of marrow fibrosis did not affect the differences observed and described above. The p-TFH cell subset was identified in every case as a memory component of CD4+ T helper cells, as previously described. Although the number of patients analyzed is limited, our results suggest that low risk MDS patients show a trend of lower CXCR5+CD4+ cells compared to age–matched control subjects. EPO treatment eliminates IL-21 production from CXCR5+CD4+ cells compared to treatment-naïve patients. Further analysis of a larger pool of subjects along with the examination of the specific transcription factor Bcl-6 will reveal the role of p-TFH cells in low risk MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Long-Shan Ji ◽  
Xue-Hua Sun ◽  
Xin Zhang ◽  
Zhen-Hua Zhou ◽  
Zhuo Yu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cells ◽  
T Helper Cells ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
T Helper ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper

Helping B cells and antibody responses is a major function of CD4+T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4+T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.

The CD40-Receptor Is Upregulated on Monocytes from Patients with Low-Risk Myelodysplastic Syndromes and Its Inhibition by a Monoclonal Anti-CD40 Antibody Can Increase Colony Formation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2640-2640
Author(s):  
Stef Meers ◽  
Ahmad Kasran ◽  
Louis Boon ◽  
Marc Boogaerts ◽  
Peter Vandenberghe ◽  
...  
Keyword(s):  
The Netherlands ◽  
Myelodysplastic Syndromes ◽  
T Helper Cells ◽  
Colony Formation ◽  
Matched Control ◽  
Tnf Alpha ◽  
T Helper ◽  
Control Subjects ◽  
Helper Cells ◽  
Stimulation Of

Abstract There is increasing evidence that the immune system can promote cytopenia in myelodysplastic syndromes (MDS) to a variable extent. The interaction between CD40 and its natural ligand CD40L (CD154) plays a critical role in the regulation of humoral and cellular immune responses. The aim of this study was to investigate the role of the CD40/CD40L interaction in the pathogenesis of MDS. For this purpose, we looked at the presence of the CD40 receptor and its ligand in MDS peripheral blood (PB) and bone marrow (BM), and we studied the in vitro effects of inhibition and stimulation of the CD40 receptor on MDS monocytes. 1) Expression of CD40/CD40L. We analysed PB samples of 40 patients with MDS (19 RCMD, 15 RCMD-RS, 3 RAEB-1, 3 5q- syndrome) and 29 age-matched control subjects by flow cytometry. We observed that MDS patients have significantly higher percentages of circulating CD40+/CD14+ cells (8.34 % +/− 1.28 vs. 2.78 % +/− 0.31, p=0.0004) and CD40L+ T helper cells (4.44 % +/− 0.52 vs. 2.16 % +/− 0.22, p=0.001). In addition, we found higher percentages of CD40+/CD14+ cells (9.47 % +/− 1.96 vs. 3.53 % +/− 0.63, p=0.03) and CD40L+ T helper cells (5.13 % +/− 0.86 vs. 2.60 % +/− 0.53, p= 0.008) in BM of 22 patients (1 RA, 11 RCMD, 4 RCMD-RS, 5 RAEB-1 and 1 5q- syndrome) compared to 11 donor samples. 2) Stimulation of CD40. Selected CD14+ cells from PB of 21 patients (1 RA, 12 RCMD, 6 RCMD-RS, 2 RAEB-1) and 25 control subjects were stimulated for 24h with LPS or an agonistic anti-human CD40 antibody (clone 64, PanGenetics NV, The Netherlands). We observed that anti-CD40 induced significantly higher TNF-alpha levels in patients than in controls (436 vs. 64 pg/mL, p=0.008), whereas LPS induced comparable TNF-alpha levels. 3) Blocking of CD40. We cultured 5x105 BM mononuclear cells of 22 patients (1 RA, 12 RCMD, 3 RCMD-RS, 4 RAEB-1 and 2 5q- syndrome) in methylcellulose supplemented with growth-factors in the presence or absence of 5D12 (antagonist chimeric monoclonal anti-human CD40 antibody, PanGenetics NV, The Netherlands). The presence of 5D12 significantly increased colony-formation at day 14 (140 vs. 112, p=0.002). 5D12 did not affect colony formation in CD14-depleted cultures, nor in controls. In conclusion, we have demonstrated elevated levels of CD40 receptor on PB and BM monocytes of patients with MDS compared to age-matched control subjects. In addition, we have demonstrated increased levels of its ligand CD40L on T helper cells in PB and BM. Stimulation of CD40 on monocytes from patients induces significantly higher TNF-alpha levels, a cytokine known to inhibit colony formation. Moreover, we demonstrated that inhibition of this CD40 receptor with 5D12 can increase colony formation and that its effect is specific monocyte-dependent. Our observation together with the proven safety of 5D12 in phase 1 trials for patients with inflammatory bowel disease, might justify a phase I trial of 5D12 to improve cytopenia in patients with MDS.

scholarly journals An Inherently Bifunctional Subset of Foxp3+ T Helper Cells Is Controlled by the Transcription Factor Eos

Immunity ◽  
2013 ◽  
Vol 38 (5) ◽  
pp. 998-1012 ◽  
Author(s):  
Madhav D. Sharma ◽  
Lei Huang ◽  
Jeong-Hyeon Choi ◽  
Eun-Joon Lee ◽  
James M. Wilson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Helper Cells ◽  
T Helper ◽  
Helper Cells

scholarly journals Essential Role of the Thymus to Reconstitute Naive (CD45RA+) T-Helper Cells After Human Allogeneic Bone Marrow Transplantation

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 850-857 ◽  
Author(s):  
Andreas Heitger ◽  
Nikolaus Neu ◽  
Hannelore Kern ◽  
Eva-Renate Panzer-Grümayer ◽  
Hildegard Greinix ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Helper Cells ◽  
Marrow Transplantation ◽  
Suppressor Cells ◽  
Allogeneic Bone ◽  
T Helper ◽  
Cd4 Cells ◽  
Helper Cells

Abstract To contribute to the understanding of the role of the thymus in humans in the reconstitution of naive (CD45RA+) T cells after bone marrow transplantation (BMT), we compared T-cell regeneration in a unique situation, namely a thymectomized cancer patient (15 years old), with that of thymus-bearing patients after allogeneic BMT. These cases shared features of transplantation (total body irradiation, HLA-matched donors, and graft-versus-host disease prophylaxis with cyclosporine A) and all had an uncomplicated posttransplantation course. As shown by fluorescence-activated cell sorting analyses, the thymectomized host failed to reconstitute CD45RA+ T-helper cells even 24 months after BMT (11% CD45RA+ of CD4+ cells). In this patient, preferentially CD45RO+ cells contributed to the recovery of CD4+ cells (206 of 261/μL at 6 months and 463 of 558/μL at 24 months after BMT, CD45RA+ of CD4+ cells), whereas CD45RA+ cells remained low (<60/μL). In contrast, nine thymus-bearing hosts (5 children and 4 adults) examined between 6 and 24 months after BMT effectively reconstituted CD4+/CD45RA+ cells according to their normal age-related range (≥28% in adults and ≥50% in children). Five of these were analyzed sequentially at 6 and 9 months after BMT. Within this period, CD45RA+ cells increasingly contributed to the recovery of CD4+ cells (median, +21%), even when total CD4+ cells decreased. With respect to T-cytotoxic/suppressor cells, the thymectomized host retained the capacity to recover CD45RA+ cells (137 of 333/μL at 6 months and 596 of 1,046/μL at 24 months after BMT, CD45RA+ of CD8+ cells), a proportion similar to that seen in thymus-bearing hosts. These findings suggest that a thymus-independent pathway exists to regenerate CD45RA+ T-cytotoxic/suppressor cells, but residual thymus is essential to reconstitute naive (CD45RA+) T-helper cells after BMT in humans.

scholarly journals Transcription factor Foxo1 is essential for IL-9 induction in T helper cells

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Sakshi Malik ◽  
Srikanth Sadhu ◽  
Srikanth Elesela ◽  
Ramendra Pati Pandey ◽  
Amanpreet Singh Chawla ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Helper Cells ◽  
T Helper ◽  
Helper Cells

scholarly journals Lack of enhanced T-helper cell function in uremic patients with circulating alloreactive antibodies.

1995 ◽  
Vol 5 (7) ◽  
pp. 1441-1450
Author(s):  
A Shoker ◽  
R Miller ◽  
R Uldall ◽  
E Friedman ◽  
S Angra ◽  
...  
Keyword(s):  
T Helper Cells ◽  
Blood Lymphocyte ◽  
Cell Function ◽  
Interleukin 2 ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper ◽  
Cd4 Cells ◽  
Helper Cells ◽  
Uremic Patients

Some uremic patients with a history of blood transfusion, pregnancy, and previous transplantation maintain high levels of alloreactive cytotoxic antibodies in the absence of continuous exogenous allogenic stimuli and are thus considered sensitized to the major histocompatibility proteins. To differentiate into antibody-producing cells, B lymphocytes must interact with T-helper (CD4+) cells. Whether ongoing help from these cells is necessary for the B cells to continue producing cytotoxic alloreactive antibodies in these sensitized uremic patients is unknown. To gain insight into the cellular mechanisms that are associated with sustained alloantibody production, T cell activation markers were measured and specific and nonspecific T-helper cell function was studied in three uremic groups with different levels of panel reactive antibodies: 10 patients whose sera reacted to more than 80% of a panel of normal lymphocytes for at least 6 months before the study were highly sensitized, 20 patients whose sera reacted to less than 80% of the panel were moderately sensitized, and 10 nonsensitized patients whose sera did not react to any cell on the panel. The number of total and activated T-helper cells was similar in the highly sensitized and nonsensitized patients. Peripheral blood lymphocyte proliferation in response to plant lectins, soluble OKT3, or alloantigens was similar in the three uremic groups. The spontaneous proliferation of pure T-helper cells and proliferative responses to immobilized OKT3 or alloantigens were also similar in highly sensitized and nonsensitized patients. Alloreactive interleukin-2-producing cell frequencies with pure CD4+ cells as responding cells were 771 +/- 77.9/10(6) cells in highly sensitized, 945 +/- 252/10(6) cells in nonsensitized, and 973 +/- 114/10(6) cells in controls (P = not significant). Panel reactive antibody levels did not correlate with any of the measures of T helper responses. There was a significant decrease of peripheral blood lymphocyte responses to alloantigens and anti-CD3 antibody in all uremic patients as compared with normals, suggesting a dysfunction in accessory cells that was quantitatively similar in sensitized and nonsensitized patients. In spite of the continuous production of alloantibodies by B cells, there is no evidence of either specific or nonspecific enhancement of T-helper cell function in sensitized patients. The absence of T cell immunity to alloantigens suggests that sustained activation of T-helper cells with subsequent interleukin-2 production is not necessary to maintain alloreactive B cell function.

scholarly journals Immunohistochemical Expression Patterns of Inflammatory Cells Involved in Chronic Hyperplastic Candidosis

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 232 ◽  
Author(s):  
Ailish Williams ◽  
David Williams ◽  
Helen Rogers ◽  
Xiaoqing Wei ◽  
Michael Lewis ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Lamina Propria ◽  
T Helper Cells ◽  
Cytotoxic T Cells ◽  
Expression Patterns ◽  
Inflammatory Cell Infiltrate ◽  
T Helper ◽  
Cd4 Cells ◽  
Helper Cells ◽  
The Mean

The profile of the inflammatory cell infiltrate in chronic hyperplastic candidosis (CHC) was determined in oral mucosal biopsies by immunohistochemistry. One tonsillar tissue section was included as an immunohistochemistry control, whilst squamous papilloma (n = 4) with secondary Candida infection was used as Candida controls. Oral lichen planus tissues (n = 10) provided negative controls for Candida presence, as well as positive controls for inflammation. Immunohistochemistry employed antibodies specific for CD3+ (T lymphocytes), CD4+ (T helper cells), CD8+ (cytotoxic T cells), and CD20+ (B lymphocytes). Manual counting of stained cells from digitised images determined the proportion of each cell type relative to the total number of cells, and these were assessed in the mucosa, the epithelium, and the lamina propria. The mean proportion of CD3+ cells was significantly higher than CD20+ cells in all tissue types. For CHC, the mean proportion of CD3+ cells in entire tissues was 15.6%, with the highest proportion in the lamina propria (32.6%) compared with the epithelium (3.9%). CD20+ cells were in much lower proportions (1.8%) in CHC, with the highest proportion (3.6%) in the lamina propria. T lymphocytes were predominately CD4+ cells (9.0%) compared with CD8+ cells (4.4%). CD4+ cells were most prevalent in the lamina propria (23.1%) compared with the epithelium (mean = 3.2%). From these results, it was concluded that the immune response invoked by Candida in CHC is primarily driven by the T helper cells.

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