Impact Of Treatment On Regulatory CD4+ T Lymphocytes, TH17 and Cytokines In Patients With Classical Hodgkin’s Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1756-1756
Author(s):  
Adriana M. Damasco Penna ◽  
Priscilla Brito Silva ◽  
Joyce M. K. Silva ◽  
Maria Mirtes Sales ◽  
Elma Maria Chaves ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Treatment Strategies ◽  
Interleukin 17 ◽  
Barr Virus ◽  
Epstein Barr ◽  
The Impact

Abstract Introduction Although immunosuppression has long been recognized in classical Hodgkin lymphoma (cHL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. Increased frequencies of regulatory CD4+ T lymphocytes in the tumor microenvironment and peripheral blood have been proposed as one of the mechanisms for this anergic state. However, little is known about the disbalance between regulatory and effector CD4+ subpopulations and cytokines in the peripheral blood of cHL patients and how treatment can modify this regulatory/effector ratio. In this study, we analyzed the regulatory and effector CD4+ subpopulations together with pro and anti-inflammatory cytokines in peripheral blood of cHL patients and the impact of treatment on these cells and cytokines. Material and Methods This is an open multicenter study and, so far, we included 54 patients from December 2009 to July 2013. Thirty-four patients have completed therapy on July 2012 and were included in this study. Blood was drawn at diagnosis and after completion of treatment (1 to 4 months). Nineteen healthy blood donors volunteers were recruited as controls. Quantification of regulatory and effector T lymphocytes was done by flow cytometry using CD3, CD8, CD4, CD25, Foxp3, CTLA4, GITR and interleukin-17 (IL17) antibodies. Ten cytokines were studied: IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, sIL-2Rα, TNF-α, IFN-γ, and VEGF. Cytokine levels were determined by multiplexed immunoassay system. All these parameters were correlated to phenotypic and clinical parameters in uni- and multivariate models pre and post-treatment. In this study, only cHL patients whose histology could be confirmed and EBV association established were studied. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. Results From the 34 cHL patients recruited for this study, 17 (50%) were male, 16 (47%) had Epstein-Barr virus (EBV) related cHL, 27 (79%) patients presented with B symptoms and 18 (53%) patients had advanced diseases at diagnosis. Results of subsets of CD4+ T cells and cytokines are summarized in the following table: After treatment, the percentage of regulatory CD4+CD25highFoxP3+ and effector CD4+IL17+ T lymphocytes were not different from diagnosis (0.9 vs 0.4, p=0.45; 0.6 vs 0.9, p=0.52; respectively) and from controls (0.9 vs 0.3, p=0.22; 0.6 vs 0.7, p=0.84; respectively). Interestingly, increased CD4+CD25highFoxP3+ T lymphocytes were correlated with advanced disease at diagnosis (p=0.03) and an erythrocyte sedimentation rate (ESR) > 30 mmHg (p=0.01). Additionally, we found a negative correlation between soluble IL-2Rα and CD4+GITR+ (p=0.02) and CD4+FOXP3+ (p=0.02). Conclusions In this study, we showed that, after treatment, there was a decrease of some subsets of CD4+ T cells with regulatory phenotype, together with a decrease of IL-6, IL-10 and sIL-2Rα. Understanding cHL associated immunosuppression and the immune reconstitution after treatment maybe the key to develop new treatment strategies, designed to manipulate regulatory activity. Further studies investigating these CD4+ T lymphocytes subpopulations with functional assays are warranted. Given that the incidence of EBV-related cHL, disease presentation and severity are different in developing countries than in developed ones, we emphasize the importance of this ongoing Brazilian multicenter project. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Human Cd4+ T Lymphocytes Consistently Respond to the Latent Epstein-Barr Virus Nuclear Antigen Ebna1

2000 ◽  
Vol 191 (10) ◽  
pp. 1649-1660 ◽  
Author(s):  
Christian Münz ◽  
Kara L. Bickham ◽  
Marion Subklewe ◽  
Ming L. Tsang ◽  
Ann Chahroudi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Cd4 T Cell ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

The Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1 is critical for the persistence of the viral episome in replicating EBV-transformed human B cells. Therefore, all EBV-induced tumors express this foreign antigen. However, EBNA1 is invisible to CD8+ cytotoxic T lymphocytes because its Gly/Ala repeat domain prevents proteasome-dependent processing for presentation on major histocompatibility complex (MHC) class I. We now describe that CD4+ T cells from healthy adults are primed to EBNA1. In fact, among latent EBV antigens that stimulate CD4+ T cells, EBNA1 is preferentially recognized. We present evidence that the CD4+ response may provide a protective role, including interferon γ secretion and direct cytolysis after encounter of transformed B lymphocyte cell lines (B-LCLs). Dendritic cells (DCs) process EBNA1 from purified protein and from MHC class II–mismatched, EBNA1-expressing cells including B-LCLs. In contrast, B-LCLs and Burkitt's lymphoma lines likely present EBNA1 after endogenous processing, as their capacity to cross-present from exogenous sources is weak or undetectable. By limiting dilution, there is a tight correlation between the capacity of CD4+ T cell lines to recognize autologous B-LCL–expressing EBNA1 and DCs that have captured EBNA1. Therefore, CD4+ T cells can respond to the EBNA1 protein that is crucial for EBV persistence. We suggest that this immune response is initiated in vivo by DCs that present EBV-infected B cells, and that EBNA1-specific CD4+ T cell immunity be enhanced to prevent and treat EBV-associated malignancies.

IL-17-Producing T Cells Contribute to Mediate Acutegraft-Versus-Disease In Patients Undergoing Unmanipulated Blood and MarrowTransplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2310-2310
Author(s):  
Xiang-Yu Zhao ◽  
Ling-Ling Xu ◽  
Sheng-Ye Lu ◽  
Kai-Yan Liu ◽  
Lan-Ping Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Tissue Injury ◽  
Tc17 Cells

Abstract Abstract 2310 Acute GVHD is a proinflammatory process mediated in part by mature donor T cells present in the stem cell or marrow inoculums that are polarized toward a Th1 phenotype and recognize minor or major histocompatibility disparities between the donor and host. A large amount of data has clearly shown that a newly identified subset of interleukin (IL)-17-producing CD4 T lymphocytes, named TH-17 cells, play a crucial role in triggering inflammation and tissue injury in various autoimmune diseases. The role of TH17 cells in acute GVHD had been controversial in recent mice and human transplantation. The aim of this study was to investigate the effects of IL17-producing T cells, including Th17 and Tc17 cells, on GVHD in patients receiving granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBPCs) and G-CSF-primed bone marrow (GBM) transplantation. Forty-one patients were analyzed according to the Th17 and Tc17 cell content in allograft in relation to aGVHD. Furthermore, ten patients with acute GVHD onset were monitored for the presence of Th17 cells by flow cytometry in the peripheral blood. Patients who subsequently developed aGVHD have greater proportions and doses of Th17 and Tc17 cells in GBM and PBPCs allograft infused into the patients (p=0.049 and 0.029 for Th17 in GBM; p=0.078 and p=0.033 for Tc17 in GBM; p=0.103 and 0.008 for Th17 in PBPCs; p=0.007 and 0.001 for Tc17 cells in PBPCs). At the same time, there were also significantly higher proportions and doses of Th1 and Tc1 cells in GBM and PBPCs allograft in patients with aGVHD compared with those levels in patients without aGVHD. Acute GVHD occurred 20 patients occurred, among which were 2 patients with gastrointestinal GVHD, 4 patients with skin plus gastrointestinal GVHD and the 14 others with simple skin GVHD. When we further compared patients according to the aGVHD target organ, we also found the significant association between dose of IL17 producing T cells (Th17 and Tc17) and the occurrence of simple skin GVHD. Cox regression models demonstrated that dose of Th17 in GBM (RR 1.095, CI 1.032– 1.162, P=0.003), dose of Tc17 in PBPCs (RR 1.063, CI 1.017– 1.112, P=0.008) and the number of HLA locus mismatch (RR 1.84, CI 1.18– 2.87, P=0.008) emerged as the independent factors influencing the occurrence of aGVHD. Patients receiving a higher dose of Th17 cells in GBM allograft (>8.5×104/kg, p=0.005), and Tc17 cells in PBPCs (>16.8×104/kg, p=0.001) exhibited a higher incidence of aGVHD. An increased Th17 population (up to 4.99% of CD4 T lymphocytes) was observed in patients with acute GVHD onset. In contrast, the percentage of Th17 cells drastically decreased in GVHD patients when they were treated to achieve partial and complete remission (p=0.013 and p=0.008, respectively). All percentages of Th17 and Tc17 were significantly reduced after G-CSF in vivo application. Our results suggest IL-17 producing T cells contribute to mediate aGVHD. Furthermore, G-CSF in vivo application helps to reduce the occurrence of aGVHD through reducing the secretion of IL17 in T cells. Disclosures: No relevant conflicts of interest to declare.

Increased CD39 Expression on CD4+ T-Lymphocytes Has Clinical and Prognostic Significance in Chronic Lymphocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3895-3895
Author(s):  
Yair Herishanu ◽  
Inbal Hazan-Hallevi ◽  
Sigi Kay ◽  
Varda Deutsch ◽  
Aaron Polliack ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Anti Inflammatory

Abstract Abstract 3895 Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes pro-inflammatory extra-cellular ATP, generates anti-inflammatory adenosine and also protects regulatory T cells from ATP-induced cell death. In this study we investigated the clinical significance of CD39 expression on CD4+T-cells in 45 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4+CD39+ lymphocytes were increased in the peripheral blood of patients with CLL (4.6%±2.28 vs. 17.3%±12.49, respectively, p=0.004), and correlated with advanced stage of disease (9.72%±5.76, 18.15%±12.03 and 25.90%±16.34, of CD4+ lymphocytes, in patients with Rai stages 0, 1+2 and 3+4, respectively, p=0.019). CD4+CD39+ cells were also higher in patients with CLL who needed therapeutic intervention (untreated; 12.99%±10.63 vs treated; 22.21%±12.88, p=0.01) and in those who were ZAP70+ or had b2-microglobulin levels>3g/L. There were more CD4+CD39+ lymphocytes in the bone marrow compartment (22.25%±16.16) than in the peripheral blood (16.60%±15.84, p=0.009). In-vitro studies showed that CD39 can be induced on CD4+cells by exposure to ATP or indirectly, following B-cell receptor (BCR) engagement (CD4+CD39+ lymphocytes increased by 1.56 fold, in the BCR engaged samples compared to their paired controls; 20.27%±11.3 vs. 13%±9.42, respectively, p=0.0006). Conclusions: Increased CD39 expression on CD4+ T-lymphocytes in CLL associates with an aggressive disease. This may reflect the ability of the leukemic cells to suppress the surrounding immune environment, and contribute to a poorer prognosis. CD39+ may also serve as a future target for the development of novel therapies with immune modulating anti–tumor agents in CLL. Disclosures: No relevant conflicts of interest to declare.

The Impact of Epstein Bar Virus On Hodgkin Lymphoma's Histopathological Patterns in Morocco

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4781-4781
Author(s):  
Soumaya Anoun ◽  
Sofia Marouane ◽  
Meryem Kabbali ◽  
Soumia Zamiati ◽  
Said Benchekroun ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Developed Countries ◽  
Histological Subtype ◽  
Male Predominance ◽  
Barr Virus ◽  
Ebv Infection ◽  
Hematoxylin Staining ◽  
Staining Protocol ◽  
Epstein Barr ◽  
The Impact

Abstract Abstract 4781 Background: In Morocco, improvement of living conditions and access to healthcare has increased life expectancy from 58 years in 1980 to 72 years in 2010. There has been a corresponding decrease in early childhood infections, including Epstein Barr virus (EBV) infection, which is associated with Hodgkin lymphoma (HL). Mixed cellularity (MC) was the most common histopathological subset of HL in Morocco. Prior studies have shown the shift to nodular sclerosis (NS) subset since 1998. Currently, the incidence of NS subtype is still predominant in our country. Our aim is to study the incidence of EBV infection in HL Moroccan population and correlate its decrease to explain the shift of HL histopathological pattern. Patients and methods: We compared children and adults with HL diagnosed during 3 periods: 1980–1995, 1998–2005 and 2010–2011 in the same university medical centre. All histological samples were prepared for examination by paraffin method, than stained by Hematoxylin staining protocol. Immunuhistochemical features of Hodgkin Reed Sternberg cells were performed to assess the expression of antibodies markers (CD30, CD15). The EBV profiling was identified by immunohistochemical stains for EBV latent membrane protein 1 (LMP-1) for the last periods. Statistical comparison of all the features was performed by Epi Info software. Results: The features of 1200 HL patients were enrolled. The average number of HL cases per year was 46 patients for the first period versus 74 patients for the last period. The mean age was respectively 24 years (range 2–64 years) for the first period, 32 years (range 2–60 years) for the second period and 34 years (range 3–76 years) for the third one. Sex-Ratio showed male predominance. The comparison of HL incidence through the age over the past 30 years is further characterized by a significant higher incidence in elderly patients (2% versus 10%), and lower incidence in young children (32% versus 7%). The expression of LMP1 in HRS is significantly reduced between the two last periods (P=0.001). LMP1 positivity is higher in patients under fifteen years than in young adults. Currently, NS is the most prevalent histological subtype with a significant increasing frequency through the three periods (p< 0.001) instead of MC subtype. (Table1). Conclusion: HL pattern in Morocco tends to be like in developed countries. The shift of HL histological subtype from CM to NS could be explained by the decrease of EBV infection in Hodgkin Reed Sternberg cells. More patients need to be enrolled to confirm this hypothesis Disclosures: No relevant conflicts of interest to declare.

Unique Role of mTOR Inhibitor, Everolimus in Inducible Regulatory T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4349-4349
Author(s):  
Tokiko Nagamura-Inoue ◽  
Yuki Yamamoto ◽  
Seiichiro Kobayashi ◽  
Kazuo Ogami ◽  
Kiyoko Izawa ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Mtor Inhibitor ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Foxp3 Expression ◽  
Induction Rate ◽  
The Impact

Abstract Abstract 4349 Background: Regulatory T cells (Tregs) play an important role in immune-tolerance to allograft. Unbalance between Tregs and effector T cells is involved in graft-versus-host disease (GvHD) and other autoimmune disorders. Adoptive use of inducible Tregs (iTregs) is a candidate immunosuppressive therapy, and major concern has been focused on sustained expression of Foxp3 in iTregs. We previously reported that iTregs can be efficiently expanded from cord blood (CB)-derived CD4+ T cells in the presence of IL2, TGFb and a mTOR inhibitor, Everolimus (Eve). However, the effect of Eve on in vitro induction of iTreg remains to be elucidated. Here we studied the impact of Eve on CB-CD4+ T cells. Methods: CD4+ T cells were prepared from CB with a purity of >95% and put into the flask coated with anti-CD3/CD28 MAb. For Treg induction, these cultures were supplemented with IL2, IL-2/TGFb, IL2/TGFb/Eve, or IL2/Eve and kept for two weeks. The resulting CD4+ T cells including variable proportion of iTregs were subjected to mixed lymphocyte reaction (MLR) along with CFSE-labeled autologous responder T cells and allogeneic dendritic cells (DCs) as stimulator. Results: The basal proportion of CD25+Foxp3+ cells in CB-CD4+ T cells was 0.60 ± 0.59%. After two weeks, the induction rate of CD25+Foxp3+CD4+ T cells was higher in the culture with IL2/TGFb/Eve than that with IL2/TGFb, but Eve itself could not significantly induce iTregs in the absence of TGFb (Figure1.). The iTreg ratio (CD25+Foxp3+ cells/total CD4+ T cells) was 79.3 ± 17.4% in the culture with IL2/TGFb/Eve, 53.1 ± 23.8% with IL2/TGFb, 35.5±18.6% with IL2/Eve and 22.7 ± 18.6% with IL2, respectively. There was no significant relationship between the dose of Eve and the iTreg ratio, but the highest ratio and induction rate of iTregs were observed at 10nM Eve. Thus, an average of 2.95 ± 2.8 ×107 iTregs was obtained from 5 ×104 CB-CD4+ T cells after two weeks of culture with IL2/TGFb/Eve. The iTreg-rich population cultured with IL2/TGFb/Eve and IL2/TGFb, but not IL2 alone, efficiently inhibited MLR triggered by allogeneic DCs (Figure 2.). These iTregs were also active in MLR using allogeneic responder T cells. Interestingly, IL2/Eve-treated CB-CD4+ T cells also inhibited MLR, irrespective of the low or moderate iTreg ratio. The inhibitory effect on MLR was much less observed by another mTOR inhibitor, rapamycin, rather than Eve (Figure2). Expression of CD26 on CD4+ T cells was inversely correlated to Foxp3 expression and significantly down-regulated by TGFb with or without Eve. Discussion: Treatment of CB-CD4+ T cells with IL2/TGFb/Eve results in the efficient ex vivo expansion of functional iTregs. Eve enhanced TGFb induction of Foxp3 expression, but did not induce Foxp3 expression by itself. mTOR is a complex of TORC1 and 2. Rapamycin is reported to inhibit TORC1, while Eve inhibits both of them, at general dose. In recent report, mTOR-deficient T cells (TORC1/2, not TORC1 alone) displayed normal activation and IL-2 production upon initial stimulation, but failed to differentiate into effecter T cells, instead, differentiated into Tregs. Although the direct mechanism to inhibit MLR by CB-CD4+ T cells treated with Eve remained to be elucidated, these results suggested the aberrant pathways of immunological inhibition. Disclosures: No relevant conflicts of interest to declare.

CD4+ctla-4+ t Lymphocytes Inversely Correlate With CD4+CD127+ T Cells In Brazilian Patients With Classical Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4240-4240
Author(s):  
Joyce M. K. Silva ◽  
Adriana M. Damasco Penna ◽  
Maria Mirtes Sales ◽  
Elma Maria Chaves ◽  
Priscilla Brito Silva ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Hodgkin Lymphoma ◽  
Cd4 T Cells ◽  
Surface Expression ◽  
Post Treatment ◽  
Healthy Controls ◽  
Classical Hodgkin Lymphoma ◽  
Epstein Barr

Abstract Introduction CD4+CTLA-4+ T lymphocytes has long been recognized as regulatory T cells, potentially decreasing antitumor immune response. Augmentation of the immune response via blockade of CTLA-4 has shown an improvement in survival for patients with metastatic melanoma, which prompted the Food and Drug Administration (FDA) approval of the CTLA-4 function blocking antibody Ipilimumab for this disease. CD4+CD127+ T lymphocytes also participate in immune homeostasis and T-cell development. The increased expression of this marker on CD4+ T cells is associated with a effector phenotype. CD127-mediated signaling in human leukemia T-cells that may be of therapeutic value, namely regarding the potential use of PI3K and mTOR pharmacological inhibitors. Increased frequencies of regulatory CD4+ cells, together with decreased effector CD4+ cells in the tumor microenvironment and peripheral blood have been proposed as one of the mechanisms for the immunosuppression state observed in classical Hodgkin lymphoma (cHL) patients. However, little is known about CD4+ T cells subsets in patients with classical Hodgkin lymphoma (cHL) and how treatment can modify these cells. Objective The aim of the study was to evaluate the surface expression of CTLA-4 and CD127 on CD4+ T cells in peripheral blood mononuclear cells (PBMC) of patients with classical Hodgkin lymphoma (cHL) at diagnosis and post-treatment and correlate these findings with clinical and epidemiological aspects. Material and Methods This is an open multicentric study and, so far, we included 54 patients from december 2009 to July 2013. Thirty-four patients have completed therapy until July 2012 and were included in this study. Blood was drawn at diagnosis and post-treatment (1 to 4 months after completion of therapy). The T cell phenotype was evaluated by flow cytometry using CD3, CD4, CD8, CTLA-4 and CD127 and correlated to phenotypic and clinical parameters in uni- and multivariate models pre and post-treatment. Nineteen healthy blood donors volunteers were recruited as controls. In this study, only cHL patients whose histology could be confirmed and Epstein-Barr (EBV) association established were studied. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. Results From the 34 cHL patients recruited for this study, 17 (50%) were male, 16 (47%) had Epstein-Barr virus (EBV) related cHL, 27 (79%) patients presented with B symptoms and 18 (53%) patients had advanced diseases at diagnosis. The percentage of CD4+ T cells with CTLA-4 surface expression was significantly increased in patients with cHL at diagnosis compared with healthy controls (median 8.7 (0.8 - 30.3) vs 2.5 (0.7 - 11.2); P<0.001). Additionally, CD4+CTLA-4+ T lymphocytes significantly decreased following treatment (8.7 (0.8 - 30.3) vs 3.9 (0.8 - 10.3); p=0.01), with values similar to healthy controls (3.9 vs 2.5; p=0.42). By contrast, CD4+CD127+ T lymphocytes were decreased at diagnosis, with values increasing after therapy (41.2 (3.3 – 75.7) vs 54.9 (17.1 – 81.3); p=0.002), similar to healthy controls (54.9 (17.1 – 81.3) vs 58.2 (41.2 – 89.8); p=0.21). The expression of CD127 on CD4+ T cells negative correlated with the expression of CTLA-4 (p<0.001). In this study, these CD4+ T cells subpopulations were neither associated with treatment response nor relapse. The frequencies of these cells were not correlated with age, gender, disease stage, erythrocyte sedimentation rate (ESR), albumin levels and EBV status. Conclusions In this study we showed a negative correlation between CTLA-4 expression on CD4+ T cells with the expression of CD127 at diagnosis of patients with cHL. These results suggest a role of CTLA-4 and CD127 on Hodgkin lymphomagenesis, possibly negatively regulating host anti-tumor immune response. Further studies investigating these CD4+ T lymphocytes subpopulations with functional assays are warranted. The promising immunotherapy regimen targeting CTLA-4 and the use of drugs that alter CD127 signaling might be beneficial in classical Hodgkin lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Virus-specific CD4+ T cells: ready for direct attack

2006 ◽  
Vol 203 (4) ◽  
pp. 805-808 ◽  
Author(s):  
Kevin N. Heller ◽  
Cagan Gurer ◽  
Christian Münz
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Barr Virus ◽  
Adaptive Immune ◽  
Infected Cells ◽  
Efficient Processing ◽  
Epstein Barr ◽  
Direct Attack

CD4+ T cells are classically thought to orchestrate adaptive immune responses. But recent studies demonstrate that they can also kill infected cells directly. A new paper shows that highly efficient processing of Epstein Barr virus (EBV) glycoproteins for presentation on MHC class II makes virus-transformed B cells susceptible to lysis by CD4+ T cells. Thus, antiviral vaccines should aim to stimulate both helper and cytolytic CD4+ T cells.

scholarly journals Detection of Epstein-Barr virus-specific memory CD4+T cells using a peptide-based cultured enzyme-linked immunospot assay

Immunology ◽  
2013 ◽  
Vol 139 (4) ◽  
pp. 533-544 ◽  
Author(s):  
Sandra A. Calarota ◽  
Antonella Chiesa ◽  
Paola Zelini ◽  
Giuditta Comolli ◽  
Lorenzo Minoli ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Specific Memory ◽  
Epstein Barr ◽  
Memory Cd4 T Cells

CD28 Fails to Costimulate Tumor-Specific Activation of Epstein Barr-Virus-Specific Memory Effector T Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1294-1294
Author(s):  
Bianca Altvater ◽  
Sibylle Pscherer ◽  
Heribert Juergens ◽  
Claudia Rossig
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Surface Expression ◽  
Effector T Cells ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Barr Virus ◽  
Epstein Barr ◽  
Signaling Domains

Abstract Genetic modification of cytotoxic T cells with tumor antigen-specific chimeric receptors (chRec) specifically redirects their effector functions towards tumor cells. Integration of the signaling domains of the costimulatory molecule CD28 into chRec enhances antigen-specific proliferation of peripheral blood-derived polyclonal human T cell populations. While CD28 plays an essential role in the priming of naïve CD4+ T cells, its contribution to effector memory cytotoxic T cell (CTL) responses is controversial. We investigated the function of chRec containing the signaling domains of CD28 in vitro expanded T cells with specificity for Epstein-Barr-virus (EBV). Chimeric T cell receptors containing an extracellular single-chain antibody domain directed against the tumor ganglioside antigen GD2 fused to the intracellular signaling domains of both the CD28 and the T cell receptor (TCR) ζ chain (14.G2a-CD28ζ), or TCRζ alone (14.G2a-ζ) were expressed in EBV-specific cytotoxic T cell (CTL) lines from three seropositive donors and in peripheral blood T cells preactivated by CD3-/CD28-specific antibody crosslinking by retroviral gene transfer. Following transduction with the chRec genes, 14.G2a-ζ and 14.G2a-CD28ζ EBV-CTL had comparable levels of chRec surface expression (21–28% versus 26–40%). EBV-CTL had an immunophenotype characteristic of memory effector T cells, coexpressing CD3 and CD45RO in the absence of CD45RA and CD27 surface expression. The transduced CTL maintained their capacity to specifically lyse autologous EBV targets in 4 hr 51Cr release assays and to proliferate after stimulation with autologous EBV targets. Intracellular cytokine staining demonstrated efficient and comparable antigen-specific IFN-γ secretion by both 14.G2a-ζ and 14.G2a-CD28ζ-transduced CTL in response to EBV and tumor targets. Furthermore, GD2+ neuroblastoma targets were lysed in a comparable and antigen-specific manner. However, while antigen engagement by 14.G2a-CD28ζ efficiently induced expansion of non-specifically activated polyclonal peripheral blood lymphocytes in an antigen-dependent manner, CD28 signaling failed to overcome the failure of transduced EBV-CTL to specifically proliferate in response to GD2+ tumor cells. Thus, the costimulatory requirement for the highly efficient proliferative activation response of EBV-specific CTL to viral antigen can not be mimicked by combined CD28 and ζ signaling. Exploring the mechanisms and costimulatory requirements of effector memory T cell reactivation may help to exploit the full potential of this highly cytolytic T cell population for adoptive immunotherapy of cancer.

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