scholarly journals T Cell Exhaustion and Senescence in Epstein-Barr Virus-Associated Lymphoma Patients

2020 ◽  
Author(s):  
Huihui Liu ◽  
Junhui Xu ◽  
Lihong Wang ◽  
Wenjun Mao ◽  
Bingjie Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Epstein Barr Virus ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Barr Virus ◽  
Cell Counts ◽  
Healthy Donors ◽  
Epstein Barr

Abstract Background The Epstein-Barr Virus (EBV) is tumorigenic, and can be detected in many kinds of lymphomas. Some studies have shown a worse prognosis for patients with EBV-associated lymphoma. However, the mechanism is not fully understood. This study aimed to investigate the T cell signatures in patients with EBV-associated lymphoma. Methods Peripheral blood was collected from 17 patients with EBV-associated lymphoma and 19 healthy donors. We first examined the proportions of the lymphocyte subpopulations in peripheral blood mononuclear cells in patients with both groups by flow cytometry. Then we employed the enzyme-linked immunospot assay to evaluate the EBV antigen-specific response of the cytotoxic T cells in the two groups. Finally, to explore the mechanism of T cells dysfunction in EBV-associated lymphoma, we examined the expression of multiple inhibitory receptors representing T cell exhaustion and biomarkers representing T cell senescence on the surfaces of CD4+ T cells and CD8+ T cells. Results The ratio of peripheral CD4+ T cells and the absolute cell counts of CD4+ T cells and CD8+ T cells were significantly decreased in patients with EBV-associated lymphoma compared with those of healthy donors. The IFN-γ production upon stimulation of EBV mixed peptides were remarkably reduced in the patients. Higher expression levels of T cell exhaustion markers, PD1, LAG3, TIM3 and CTLA4 on T cells were found in the patients. The two subsects of exhausted T cells (T-bethiPD1mid and EOMEShiPD1hi) were higher in the patients. More importantly, CXCR5+CD8+T cells controlling viral replication decreased significantly in the patients. The fractions of senescent T cells increased in the patients. Conclusions In summary, our study demonstrated that the reduced EBV-specific T cells, the exhaustion and senescence of T cells together contributed to the T cell dysfunction in the patients with EBV-associated lymphoma.

T Cell Exhaustion Contributes to Immune Evasion in Chronic Lymphocytic Leukaemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1773-1773
Author(s):  
Franz Josef Gassner ◽  
Nadja Zaborsky ◽  
Daniel Neureiter ◽  
Michael Huemer ◽  
Alexander Egle ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Peripheral Blood ◽  
Lymphocytic Leukaemia ◽  
Tumour Cells ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Healthy Donors

Abstract Abstract 1773 T cell exhaustion is a state of T cell dysfunction in response to chronic antigen exposure, marked by impaired effector function and the continued expression of inhibitory receptors such as Programmed Death 1 (PD-1) (Wherry EJ. Nat Immunol. 2011 Jun;12(6):492–9.). Because tumour growth in chronic lymphocytic leukaemia (CLL) occurs over a long period of time, we hypothesized that the continued exposure of T cells to a CLL-derived antigen could also lead to a state of T cell exhaustion. We therefore investigated whether T cell exhaustion is induced in CLL by using the Eμ-TCL1 transgenic (tcl1tg) tumour transfer mouse model for this disease (Hofbauer JP, et al. Leukemia. 2011 Sep;25(9):1452-8) and by analyzing primary samples from CLL patients. We found that the number of PD-1+ T cells was increased in both CD4+ and CD8+ populations and in all lymphoid compartments examined of the Eμ-TCL1 transgenic (tcl1tg) tumour recipient mice, but not in recipient mice receiving wildtype (WT) splenocytes showing that leukemic mice have an increased number of T cells displaying an exhausted phenotype that is induced by the presence of CLL cells. We next assessed the expression of the ligands for PD-1 on the surface of murine CLL cells. Peripheral CLL tumour cells showed only a modest increase in PD-L1 expression as compared to WT B cells. However, lymph node and spleen residing tumour cells showed a marked increase in PD-L1 expression, which suggests a microenvironment-induced upregulation of PD-L1 on tumour cells, e.g. by their close contact to accessory cells. To validate our results on primary human CLL samples, we collected peripheral blood from 89 unselected CLL patients and 18 healthy donors and observed an increase in surface expression of PD-1 on the CD4+ and CD8+ T cell populations. While the percentage of PD-1+ CD4+ T cells in chemonaive patients was comparable to healthy donors, chemotherapy drastically increased the number of PD-1-expressing CD4+ T cells (63.81% ±19.75 vs 35.70% ±19.22; p<.001). In contrast, treatment apparently had little impact on the PD-1+ CD8+ population, indicating that PD1 induction on CD8+ T cells might be a more general CLL specific phenomenon. PD-1 expression in chemonaive patients did not correlate with the prognostic markers CD38, Zap-70 and IgVH mutations, however, it significantly correlated with Rai stage (CD4+: p<.001; CD8+: p=.003; spearman correlation). Our immune phenotyping analyses also included markers to distinguish between naïve, memory, and effector T cell subsets. We observed that PD-1 expressing T cells belong primarily to the memory compartment, characterized by the absence of CD45RA expression. PD-1 expression levels in T cells was independent from chronic human cytomegalovirus (HCMV) infection, indicating that increased PD-1+ T cell numbers in CLL do not simply reflect a higher incidence of HCMV infections, which has been described in this patient population. As we speculated that PD1/PDL1 pathway might be exploited by CLL to evade a T cell dependent cytotoxic attack, we next wanted to know whether blocking this pathway by recombinant PD1 (rPD1) or PD-L1 specific Fab fragments in vivo would lead to reinvigoration of CLL specific T cells reflected in CLL clearance. We found that inhibition of PD1/PD-L1 binding in vivo in the tcl1tg tumour transfer model led to a decrease in CLL load in the peripheral blood and in all analysed organs (lymph node, spleen, bone marrow, liver, lung) while in vitro treatment with rPD-1 or PD-L1 Fab fragment did not affect the viability of mouse tumour cells. Our results imply that in tumour bearing mice, a vast number of tumour-specific exhausted CTLs exist that can be immediately reactivated by PD1/PD-L1 blockage leading to cytolysis of the tumour, thereby representing a promising target for therapeutic intervention in CLL patients. Disclosures: No relevant conflicts of interest to declare.

Infusion Of Donor-Derived CD19-Redirected-Virus-Specific T Cells For B-Cell Malignancies Relapsed After Allogeneic Stem Cell Transplant: A Phase I Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 152-152 ◽  
Author(s):  
Conrad Russell Y. Cruz ◽  
Kenneth P. Micklethwaite ◽  
Barbara Savoldo ◽  
Carlos A. Ramos ◽  
Sharon Lam ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Relapsed Disease ◽  
Anti Tumor Activity

Abstract Donor lymphocyte infusions (DLI) following hematopoietic stem cell transplantation may reduce or control opportunistic infections and leukemia/lymphoma relapse, but the associated graft versus host disease (GvHD) limits the clinical success of this procedure. Since T cell immunotherapy may be a safer alternative to DLI we have now used a single T cell platform that mediates both antileukemic and antiviral activity. Autologous T cells modified to express CD19-specific chimeric antigen receptors (CD19.CAR) have had clinical activity against CD19-expressing malignancies, but it is unknown if similarly modified allogeneic T cells will be equally effective. Allogeneic virus specific T cells (VSTs) directed to cytomegalovirus (CMV), adenovirus (Adv), and Epstein Barr virus (EBV) have been shown to be safe and effective in preventing and treating life-threatening viral infections post HSCT. Therefore, we sought to determine whether allogeneic VSTs could be engineered to express CD19.CAR and would retain the safety and effectiveness of unmodified VSTs whilst gaining anti-tumor activity. VSTs were expanded ex vivo using antigen presenting cells engineered to express adenovirus and cytomegalovirus (using an Ad5f35 adenoviral vector expressing the CMV pp65 gene), and Epstein Barr virus (using EBV-infected lymphoblastoid cell lines) antigens. After 3 stimulations, the VST’s were modified to express CD19.CAR.28ζ using a retroviral vector encoding the CAR-CD19 receptor coupled to the CD28 co-stimulatory molecule and the T cell receptor zeta (ζ) chain. Nine CD19.CAR-modified virus specific T cell (CD19.CAR-VSTs) products were generated for infusion. All VST lines recognized at least one viral antigen as determined by Elispot or chromium release assays and 20% to 48% of cells expressed the CD19.CAR. All lines killed CD19-expressing cells in vitro. We treated nine patients with these CD19.CAR-VSTs, 3 months to 13 years after HSCT. Six patients received CD19.CAR-VSTs for relapsed disease and 3 patients received the T cells as adjuvant therapy to prevent viral infection and relapse after HSCT. Safety. There were no infusion-related toxicities. One patient presented with gastrointestinal symptoms following infusion subsequently determined to be unrelated to the T cells. Persistence. VSTs persisted a median of 8 weeks in the peripheral blood and up to 9 weeks at disease sites. In three patients (#1, #3 and #5), CD19.CAR signals were detectable in the bone marrow or the lymph nodes (44.8, 25.85, and 32 copies/1000 ng DNA) even when no signal was measurable in peripheral blood, indicating preferential accumulation of the infused T cells at the disease site. Anti-Tumor Activity. During the period of CD19.CAR-VST persistence, objective anti-tumor activity was evident in 2/6 patients with relapsed disease (patient # 1 had detectable blasts in the peripheral blood which disappeared within 1-2 weeks following infusion, patient # 2 had 16% circulating CLL cells which decreased within 2 weeks of T cell infusion) but disease recurred after 3 and 2 months, respectively. The two patients who received cells while in remission remain disease-free >3 and >9 months later. Anti-Viral Activity. In two patients with EBV reactivation, donor CD19.CAR-VSTs expanded concomitant with an increase in virus-specific T cell responses, and decreased viral load. A third patient had a rise in adenovirus specific VSTs during an episode of adenovirus associated diarrhea. Although the infection was controlled, there was no concomitant rise in CD19-CAR expressing T cells in this patient. No other patient had viral disease. In conclusion, allogeneic CD19.CAR-VSTs administered after allogeneic HSCT are safe and can exert both anti-tumor and anti-viral activity in the absence of GvHD. Earlier administration of CD19.CAR-VSTs after HSCT, when the host is lymphodepleted and the incidence of viral infection is higher, may allow these cells to better capture the potential advantages of native TCR stimulation (and associated co-stimulation) for expansion and persistence, and thereby produce a higher frequency of sustained tumor responses. Alternatively, intentional stimulation of the native TCRs by viral vaccines may produce equal benefit, with greater predictability. Disclosures: Savoldo: Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding; Cell Medica: Patents & Royalties. Rooney:Cell Medica: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

Peripheral T-cell Lymphoma, NOS With Epstein-Barr Virus Positivity in an Elderly Patient With Myelodysplastic Syndrome: An Autopsy Case Report

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S81-S81
Author(s):  
J Lanceta ◽  
W Xue ◽  
M Hurford ◽  
H Wu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Abstract Casestudy Epstein-Barr virus (EBV)-associated peripheral T-cell lymphomas are a group of aggressive neoplasms with a geographic predilection for South America and Asia, but are very rare in Western populations. Results We report a case of a 74-year-old Caucasian female who presented with pancytopenia and B symptoms with EBV-IgG detected on admission. Past medical history included: ITP, chronic urticaria, and recently diagnosed myelodysplastic syndrome (MDS) on bone marrow biopsy one month prior to admission. Excisional biopsies of an enlarged right neck lymph node (repeated within 6 months) and right axillary lymph node five years ago were negative for a lymphoproliferative disorder at the time. Repeated bone marrow biopsy, performed during the current admission, confirmed the diagnosis of MDS, with scattered T-cells without aberrant immunophenotype. Despite aggressive treatment from multiple specialties, the patient deteriorated and expired four weeks later from complications of MDS. At autopsy, there was diffuse lymphadenopathy involving the mediastinum, axilla, pelvis and peripancreatic fat. Lymph node sections demonstrated nodal architecture effacement by diffuse, vaguely nodular lymphoid infiltrates. Histologically, the infiltrates were composed of medium to large lymphocytes with round to slight irregular nuclei, rare Reed-Sternberg-like multinucleated cells, clumped chromatin, and indistinct nucleoli. Individual cell necrosis was abundant with mitotic figures readily identifiable. Immunohistochemistry revealed CD2+ CD3+ neoplastic T-cells that co-express MUM1 and a subset of CD30, while negative for CD4, CD5, CD8, CD56, ALK1, and TDT. EBV-encoded RNA in-situ hybridization was focally positive. The final postmortem diagnosis was peripheral T-cell lymphoma, not otherwise specified (NOS), with focal EBV positivity. Conclusion Co-existence of a de-novo MDS and non-Hodgkin lymphoma without any prior chemotherapeutic exposure is a highly unusual finding, although MDS-like presentations can occur with EBV-associated lymphomas. Peripheral T-cell lymphoma, NOS is an aggressive lymphoma and EBV positivity has been found correlated with a poor prognosis. This case demonstrates how postmortem examination remains an important tool in clinical- pathological correlation and highlights the potential pathogenetic role EBV plays in MDS and T-cell lymphoma.

scholarly journals VitaminD3 Regulates T Cell Immune Responses in Allergen and Rhinovirus Induced Asthma

2021 ◽  
Author(s):  
Susetta Finotto ◽  
Patricia Haag ◽  
Darja Andreev ◽  
Nina Li ◽  
Alexander Kiefer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Murine Model ◽  
Peripheral Blood ◽  
Serum Levels ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Asthmatic Children ◽  
Rhinovirus Infection

Abstract Background: Serum 25(OH)-Vitamin D3 (VitD3) deficiency during infancy has been associated with asthma. The potential therapeutic role of VitD3 given in the airways and its interference with the allergen and Rhinovirus was the objective of this study. Methods: In two cohorts of children with and without asthma, serum levels of the C-reactive protein (CRP) were correlated to Serum VitD3 and in peripheral blood T cell inhibitor marker Programmed cell death protein 1 (PD1) mRNA was analyzed. In a murine model, VitD3 was given intranasally in vivo and in vitro to lung cells with allergen and Rhinovirus. Results: In the cohorts of pre-school age children without (control) asthma, CRP and VitD3 levels inversely correlated. In preschool asthmatic children that did not receive VitD3 supplementation as infant had more episode of asthma exacerbation associated with high CRP serum level. In peripheral blood cells from control but not asthmatic children with higher serum levels of VitD3 had lower PD1 mRNA levels. In murine model, OVA intranasal challenge induced Innate Lymphoid Cells type 2 (ILC2)-associated markers and Eosinophils in BALF and VitD3 inhibited lung inflammation and ILC2 markers. Furthermore, VitD3 given intranasally, induced CD4+T cells and reduced PD1, T regulatory cells in the lung. Similarly, VitD3 had a suppressive role on CD4+PD1+ T cells involved in T cell exhaustion in the airways in the absence of ST2 after Rhinovirus infection. Conclusion: These data support an inhibitory role of VitD3 on T cell exhaustion after allergen and rhinovirus infection that is relevant for pediatric asthma.

Infusion of Cytotoxic T Cells for the Prevention and Treatment of Epstein-Barr Virus–Induced Lymphoma in Allogeneic Transplant Recipients

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1549-1555 ◽  
Author(s):  
Cliona M. Rooney ◽  
Colton A. Smith ◽  
Catherine Y.C. Ng ◽  
Susan K. Loftin ◽  
John W. Sixbey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Mononuclear Cells ◽  
Cytotoxic T Cells ◽  
Marker Gene ◽  
Barr Virus ◽  
Immunoblastic Lymphoma ◽  
Epstein Barr ◽  
T Cell Lines

Abstract Epstein-Barr virus (EBV) causes potentially lethal immunoblastic lymphoma in up to 25% of children receiving bone marrow transplants from unrelated or HLA-mismatched donors. Because this complication appears to stem from a deficiency of EBV-specific cytotoxic T cells, we assessed the safety and efficacy of donor-derived polyclonal (CD4+ and CD8+) T-cell lines as immunoprophylaxis and treatment for EBV-related lymphoma. Thirty-nine patients considered to be at high risk for EBV-induced lymphoma each received 2 to 4 intravenous infusions of donor-derived EBV-specific T lymphocytes, after they had received T-cell–depleted bone marrow from HLA-matched unrelated donors (n = 33) or mismatched family members (n = 6). The immunologic effects of this therapy were monitored during and after the infusions. Infused cells were identified by detection of the neo marker gene. EBV-specific T cells bearing theneo marker were identified in all but 1 of the patients. Serial analysis of DNA detected the marker gene for as long as 18 weeks in unmanipulated peripheral blood mononuclear cells and for as long as 38 months in regenerated lines of EBV-specific cytotoxic T cells. Six patients (15.5%) had greatly increased amounts of EBV-DNA on study entry (&gt;2,000 genome copies/106 mononuclear cells), indicating uncontrolled EBV replication, a complication that has had a high correlation with subsequent development of overt lymphoma. All of these patients showed 2 to 4 log decreases in viral DNA levels within 2 to 3 weeks after infusion and none developed lymphoma, confirming the antiviral activity of the donor-derived cells. There were no toxic effects that could be attributed to prophylactic T-cell therapy. Two additional patients who did not receive prophylaxis and developed overt immunoblastic lymphoma responded fully to T-cell infusion. Polyclonal donor-derived T-cell lines specific for EBV proteins can thus be used safely to prevent EBV-related immunoblastic lymphoma after allogeneic marrow transplantation and may also be effective in the treatment of established disease. © 1998 by The American Society of Hematology.

High incidence of hematologic malignancy relapse after allogeneic transplantation in patients with low Epstein-Barr virus–specific T-cell counts

Cytotherapy ◽  
2019 ◽  
Vol 21 (8) ◽  
pp. 886-894 ◽  
Author(s):  
MEHUL GUPTA ◽  
SUNAND KANNAPPAN ◽  
AMIT KALRA ◽  
CYNTHIA LAM ◽  
POONAM DHARMANI-KHAN ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Hematologic Malignancy ◽  
Allogeneic Transplantation ◽  
Barr Virus ◽  
Cell Counts ◽  
High Incidence ◽  
Epstein Barr

scholarly journals Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation.

1983 ◽  
Vol 157 (1) ◽  
pp. 173-188 ◽  
Author(s):  
F Hasler ◽  
H G Bluestein ◽  
N J Zvaifler ◽  
L B Epstein
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Gamma Interferon ◽  
Barr Virus ◽  
T Cell Regulation ◽  
Epstein Barr

T cells of patients with rheumatoid arthritis (RA) do not control the rate of B lymphoblast transformation induced by Epstein-Barr virus (EBV) as efficiently as T cells from healthy individuals; thus, lymphoblast cell lines are established more readily in RA lymphocytes in vitro after EBV infection. In the present experiments, we have asked whether this T cell regulation can be reproduced by lymphocytes. We found that normal T cells, activated in allogeneic or autologous mixed leukocyte reactions (MLR), produce lymphokines that inhibit in vitro EBV-induced B cell proliferation. Allogeneic MLR supernatants inhibited EBV-induced DNA synthesis 62 +/- 4% (mean +/- SE) at 10 d post-infection, whereas autologous MLR supernatants suppressed it 50 +/- 3%. RA T cell supernatants produced in an allogeneic MLR suppressed as well as normal T cell supernatants (64 +/- 5% inhibition). In contrast, supernatants from RA autologous MLR had little inhibitory activity. EBV-induced DNA synthesis at 10 d was reduced only 8 +/- 3%, compared with the 50 +/- 3% suppressive activity of normal autologous MLR supernatants. The magnitude of the proliferative responses in the autologous MLR regenerating the lymphokines was similar in the normal and RA populations. After depletion of adherent cells from the RA auto-MLR stimulators, supernatant inhibitory activities increased to normal levels (from 11 +/- 6 [SE] to 52 +/- 6% [SE]). The inhibitory factor involved in the regulation of in vitro EBV infection is a protein with a molecular weight of approximately 50,000. Its activity is eliminated by hearing at 56 degrees C and by exposure to acid at pH 2. The inhibitory activity is blocked by mixing the MLR supernatants with a polyvalent antisera or monoclonal antibodies specific for human gamma interferon. Gamma interferon produced by activating T cells in allo- or auto-MLR can reproduce T cell-mediated regulation of EBV-induced B cell proliferation, and the failure of RA auto-MLR to generate that lymphokine parallels the defective T cell regulation of EBV-induced B cell proliferation characteristic of RA lymphoid cells.

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