scholarly journals Lack of B Lymphocytes Enhances CD8 T Cell-Mediated Resistance against Respiratory Viral Infection but Compromises Memory Cell Formation

2019 ◽  
Vol 94 (3) ◽  
Author(s):  
Pritesh Desai ◽  
Jessica Stanfield ◽  
Vikas Tahiliani ◽  
Georges Abboud ◽  
Shahram Salek-Ardakani
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Viral Infection ◽  
B Cell ◽  
Cd8 T Cells ◽  
Host Resistance ◽  
Memory Cell ◽  
Cd8 T Cell ◽  
Respiratory Viral Infection

ABSTRACT Following a respiratory virus infection, CXCR3hi CX3CR1lo and CXCR3lo CX3CR1hi CD8 T cells localize to different compartments within the lung and play an important role in host resistance, but mechanisms governing their optimal generation are poorly defined. We serendipitously found that B cell-deficient (μMT−/−) mice were highly resistant to lethal infection with a virulent poxvirus strain and that depletion of CD8 T cells rendered these mice susceptible to infection. B cells were not required for the expansion of virus-specific CD8 T cells, but a greater proportion of activated CD8 T cells acquired an effector-like CXCR3lo CX3CR1hi phenotype in the absence of B cells. After recovery from infection, CD8 T cells in μMT−/− mice contracted normally but failed to survive and seed the memory cell pool in both the lungs and spleen. These findings reveal a previously unappreciated role for B cells in regulating the balance between CD8 T cell-mediated resistance against respiratory viral infection and memory cell development. IMPORTANCE B cells play critical role in host resistance against many respiratory viral infections. However, the role of B cells beyond antibody-producing cells is less well defined. In this study, we made a surprising observation that mice lacking B cells were more resistant to respiratory infection with vaccinia virus than wild-type mice. This enhanced resistance was mediated by CD8 T cells because when we depleted CD8 T cells in B cell-deficient mice, these mice were unable to survive the infection. Interestingly, CD8 T cells in B cell-deficient mice were skewed more toward effector phenotype and less toward memory phenotype, which resulted in severely compromised memory CD8 T cell development. Thus, our study shows a novel role of B cells as regulators of CD8 T cell-mediated host resistance and memory CD8 T cell formation during respiratory viral infection.

scholarly journals Obligatory Requirement for Antibody in Recovery from a Primary Poxvirus Infection

2006 ◽  
Vol 80 (13) ◽  
pp. 6339-6344 ◽  
Author(s):  
Geeta Chaudhri ◽  
Vijay Panchanathan ◽  
Horst Bluethmann ◽  
Gunasegaran Karupiah
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ectromelia Virus ◽  
B Cell Function

ABSTRACT To understand the correlates of protective immunity against primary variola virus infection in humans, we have used the well-characterized mousepox model. This is an excellent surrogate small-animal model for smallpox in which the disease is caused by infection with the closely related orthopoxvirus, ectromelia virus. Similarities between the two infections include virus replication and transmission, aspects of pathology, and development of pock lesions. Previous studies using ectromelia virus have established critical roles for cytokines and effector functions of CD8 T cells in the control of acute stages of poxvirus infection. Here, we have used mice deficient in B cells to demonstrate that B-cell function is also obligatory for complete virus clearance and recovery of the host. In the absence of B cells, virus persists and the host succumbs to infection, despite the generation of CD8 T-cell responses. Intriguingly, transfer of naive B cells or ectromelia virus-immune serum to B-cell-deficient mice with established infection allowed these animals to clear virus and fully recover. In contrast, transfer of ectromelia virus-immune CD8 T cells was ineffective. Our data show that mice deficient in CD8 T-cell function die early in infection, whereas those deficient in B cells or antibody production die much later, indicating that B-cell function becomes critical after the effector phase of the CD8 T-cell response to infection subsides. Strikingly, our results show that antibody prevents virus from seeding the skin and forming pock lesions, which are important for virus transmission between hosts.

scholarly journals The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Caterina Veroni ◽  
Francesca Aloisi
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Epstein Barr

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

scholarly journals An Optimized CD4 T-Cell Response Can Control Productive and Latent Gammaherpesvirus Infection

2004 ◽  
Vol 78 (13) ◽  
pp. 6827-6835 ◽  
Author(s):  
Rebecca L. Sparks-Thissen ◽  
Douglas C. Braaten ◽  
Scott Kreher ◽  
Samuel H. Speck ◽  
Herbert W. Virgin
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell

ABSTRACT CD4 T cells are important for control of infection with murine gammaherpesvirus 68 (γHV68), but it is not known whether CD4 T cells function via provision of help to other lymphocyte subsets, such as B cells and CD8 T cells, or have an independent antiviral function. Moreover, under conditions of natural infection, the CD4 T-cell response is not sufficient to eliminate infection. To determine the functional capacities of CD4 T cells under optimal or near-optimal conditions and to determine whether CD4 T cells can control γHV68 infection in the absence of CD8 T cells or B cells, we studied the effect of ovalbumin (OVA)-specific CD4 T cells on infection with a recombinant γHV68 that expresses OVA. OVA-specific CD4 T cells limited acute γHV68 replication and prolonged the life of infected T-cell receptor-transgenic RAG (DO.11.10/RAG) mice, demonstrating CD4 T-cell antiviral activity, independent of CD8 T cells and B cells. Despite CD4 T-cell-mediated control of acute infection, latent infection was established in DO.11.10/RAG mice. However, OVA-specific CD4 T cells reduced the frequency of latently infected cells both early (16 days postinfection) and late (42 days postinfection) after infection of mice containing CD8 T cells and B cells (DO.11.10 mice). These results show that OVA-specific CD4 T cells have B-cell and CD8 T-cell-independent antiviral functions in the control of acute infection and can, in the absence of preexisting CD8 T-cell or B-cell immunity, inhibit the establishment of gammaherpesvirus latency.

IMMU-36. B CELL-VACCINE ELICITS LONG TERM IMMUNITY AGAINST GLIOBLASTOMA VIA ACTIVATION AND DIFFERENTIATION OF TUMOR-SPECIFIC CD8+ MEMORY T CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi100-vi100
Author(s):  
David Hou ◽  
Brandyn Castro ◽  
Mark Dapash ◽  
Aida Rashidi ◽  
Peng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Tumor Bearing

Abstract While immunotherapy is used clinically to treat many cancers, its translation into brain tumors remains elusive. The importance of B cells in cancer immunity has become increasingly clear, and we previously developed a B cell-based cellular vaccine (BVax) against glioblastoma (GBM) by further activating 4-1BBL+ B cells with CD40 agonism and IFNγ. BVax were characterized as professional antigen-presenting cells (APCs) that promote CD8+ T cell migration and persistence in murine tumor-bearing brains. This study seeks to understand the mechanisms underlying BVax-induced CD8+ T cell fitness in the tumor microenvironment. Initial transcriptomic analysis highlighted that Bvax express high levels of IL15Rα, indicating their potential ability to trans-present IL15. Considering IL15 trans-presentation is fundamental in T-cell memory differentiation, we used BVax to induce T cell activation in the presence of exogenous IL15. BVax were better capable of activating antigen-specific CD8+ T cells and promoting a memory phenotype when compared to other professional APCs such as dendritic cells (DCs). T cell receptor (TCR) CDR3β sequencing showed that BVax expanded a number of TCR clones in-vitro that were found in brains of CT2A tumor-bearing mice in-vivo. These BVax-activated CD8+ T cells displayed a stronger antigen recall response and unique metabolic profile compared to DC-activated CD8+ T cells as shown by metabolomic analysis of tumor-infiltrating CD8+ T cells. When comparing the anti-tumor effects of CD8+ T cells activated by various APCs, BVax with exogenous IL15 promoted CD8+ T cells that displayed the most potent cytotoxicity against GBM cells in-vitro. Collectively, this study suggests that the IL15/IL15Rα axis and interactions with CD8+ T cell are key factors of BVax therapy in promoting a robust survival benefit and long-term immunologic memory against GBM in preclinical models. Additionally, the development of T cell therapies based on B cell licensing can be a promising future approach for glioblastoma therapy.

scholarly journals Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine

2021 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Sloan A. Lewis ◽  
Brianna Doratt ◽  
Allen Jankeel ◽  
Izabela Ibraim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Natural Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses

mRNA based vaccines for SARS-CoV-2 have shown exceptional clinical efficacy providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4 T cells, and robust antigen-specific polyfunctional CD4 T cell responses in all vaccinees. On the other hand, CD8 T cell responses were both weak and variable. Interestingly, clonally expanded CD8 T cells were observed in every vaccinee, as observed following natural infection. TCR gene usage, however, was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response where early CD4 T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8 T cells, together capable of contributing to future recall responses.

scholarly journals Role of PD-1 during effector CD8 T cell differentiation

2018 ◽  
Vol 115 (18) ◽  
pp. 4749-4754 ◽  
Author(s):  
Eunseon Ahn ◽  
Koichi Araki ◽  
Masao Hashimoto ◽  
Weiyan Li ◽  
James L. Riley ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Lcmv Infection

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti–PD-L1 or anti–PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

Rituximab Administration before Allogeneic HSCT Is Associated with Accelerated T Cell Reconstitution after Transplantation: Kinetic Evidence for a Graft-Versus-Leukemia Effect

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3905-3905
Author(s):  
Sakura Hosoba ◽  
Christopher R. Flowers ◽  
Catherine J Wu ◽  
Jens R. Wrammert ◽  
Edmund K. Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Post Transplant ◽  
T Cell Reconstitution ◽  
Relative Value ◽  
History Of

Abstract Introduction: Rituximab (R) administration results in depletion of blood B cells and suppression of B cell reconstitution for several months after, with suggestions that T cell reconstitution may also be impaired. We hypothesized that pre-transplant R would be associated with delayed B and T cell reconstitution after allo-HSCT compared with non-R-treated allo-HSCT recipients. Methods: We conducted a retrospective analysis of 360 patients who underwent allo-HSCT using BM or G-CSF mobilized PB. Recipients of cord blood, T cell depleted grafts and 2nd allo-HSCT were excluded. Analysis of lymphocyte subsets in at least one blood at 1, 3, 6, 12, and 24 months post-allo-HSCT was available for 255 eligible patients. Data on lymphocyte recovery was censored after DLI or post-transplant R therapy. Post-HSCT lymphocyte recovery in 217 patients who never received R (no-R) was compared to 38 patients who had received R before allo-HSCT (+R) including 12 CLL, 19 NHL, and 7 B-cell ALL patients. +R patients received a median of 9 doses of R with the last dose of R at a median of 45 days pre-transplant. Results: Mean lymphocyte numbers in the blood at 1, 3, 6, 12, and 24 months were B-cells: 55 ± 465/µL, 82 ± 159/µL, 150 ± 243/µL, 255 ± 345/µL, and 384 ± 369/µL (normal range 79-835); and T-cells: 65 ± 987/µL, 831 ± 667/µL, 1058 ± 788/µL, 1291 ± 985/µL, and 1477 ± 1222/µL (normal range 675-3085). Lymphocyte reconstitution kinetics did not vary significantly based upon the intensity of the conditioning regimen or related vs. unrelated donors allowing aggregation of patients in the +R and no-R groups (Figure). B cell reconstitution in the +R patients was higher at 1 month post-allo-HSCT (relative value of 143% p=0.008) and lower at 3 months post-transplant (19.2%, p=0.069) compared to no-R patients. Blood B cells in the +R group rebounded by the 6th month post-allo-HSCT and remained higher than the no-R group through the 24th month post-HSCT (197% at the 6th month, p=0.037). Higher levels of B-cells at 1 month in the +R group was due to higher blood B-cells at 1 month post-HSCT among 12 CLL patients compared with no-R patients (423%, p<0.001; Figure), while B-cell counts in the remaining +R patients (B-cell NHL and B-cell ALL) were lower than the no-R patients at both 1 and 3 months. Reconstitution of CD4+ and CD8+ T cells among +R patients were similar to no-R patients in the first month post-allo-HSCT and then rebounded to higher levels than the no-R group of patients (relative value 194%, p=0.077 at the 24th month for CD4+ T cell subset, and 224%, p=0.020 for CD8+ T cell subset; Figure). CLL patients had a striking increase in blood levels of donor-derived CD4+ and CD8+ T cells at 3 months post-transplant concomitant with the disappearance of blood B cells compared with no-R patients (relative value of 178% and 372%, p=0.018 and p=0.003, respectively; Figure). Long term T cell reconstitution remained higher for +R patients compared with no-R patients, even when CLL patients were excluded (relative value of 203%, p=0.005 at 24 months post-HSCT; Figure). Conclusions: We observed higher levels of blood B cells and T cells ³ 6 months post-allo-HSCT in +R patients compared with no-R patients. B cell recovery at 6 months post-transplant is consistent with clearance of residual plasma R given the 1-2 months half-life of R, and the median of 1.5 months between the last dose of R and allo-HSCT. The increased blood CD8+ T cells in the blood of CLL patients at 3 months post-allo-HSCT associated with clearance of the B-cells seen 1 month post-HSCT is consistent with a donor T cell-mediated GVL effect. Pre-transplant R therapy does not appear to have any long-term deleterious effect on immune reconstitution, indicating that post-allo-HSCT vaccination at ≥6 months may be efficacious. Figure: Kinetics of lymphocyte reconstitution after allo-HSCT varied by history of pre-transplant R administration and primary disease. Panels show mean counts of each lymphocyte subset at 1, 3, 6, 12 and 24 months post-allo-HSCT for: (1) B cell, (2) T cell, (3) CD4+ and (4) CD8+ T cells. Solid lines with triangle show no-R group; dashed lines with circles shows subgroups of CLL and NHL/ALL +R patients. Asterisks show p values from t-test of the comparison between CLL +R or the NHL/ALL +R patients with no-R patients. *p<0.05; ** p<0.01; *** p<0.001. Figure:. Kinetics of lymphocyte reconstitution after allo-HSCT varied by history of pre-transplant R administration and primary disease. Panels show mean counts of each lymphocyte subset at 1, 3, 6, 12 and 24 months post-allo-HSCT for: (1) B cell, (2) T cell, (3) CD4+ and (4) CD8+ T cells. Solid lines with triangle show no-R group; dashed lines with circles shows subgroups of CLL and NHL/ALL +R patients. Asterisks show p values from t-test of the comparison between CLL +R or the NHL/ALL +R patients with no-R patients. *p<0.05; ** p<0.01; *** p<0.001. Disclosures No relevant conflicts of interest to declare.

Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1063-1070 ◽  
Author(s):  
Mohammad-Reza Rezvany ◽  
Mahmood Jeddi-Tehrani ◽  
Hans Wigzell ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cd8 T Cells ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Abstract T-cell receptor–B-variable (TCR-BV) gene usage and the CDR3 size distribution pattern were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) in patients with B-cell chronic lymphocytic leukemia (B-CLL) to assess the T-cell repertoire. The use of TCR-BV families in CD4 and CD8 T cells stimulated with autologous activated leukemic cells was compared with that of freshly obtained blood T cells. Overexpression of individual TCR-BV families was found in freshly isolated CD4 and CD8 T cells. Polyclonal, oligoclonal, and monoclonal TCR-CDR3 patterns were seen within such overexpressed native CD4 and CD8 TCR-BV families. In nonoverexpressed TCR-BV families, monoclonal and oligoclonal populations were noted only within the CD8 subset. After in vitro stimulation of T cells with autologous leukemic B cells, analyses of the CDR3 length patterns showed that in expanded TCR-BV populations, polyclonal patterns frequently shifted toward a monoclonal/oligoclonal profile, whereas largely monoclonal patterns in native overexpressed TCR-BV subsets remained monoclonal. Seventy-five percent of CD8 expansions found in freshly obtained CD8 T cells further expanded on in vitro stimulation with autologous leukemic B cells. This suggests a memory status of such cells. In contrast, the unusually high frequency of CD4 T-cell expansions found in freshly isolated peripheral blood cells did not correlate positively to in vitro stimulation as only 1 of 9 expansions continued to expand. Our data suggest that leukemia cell–specific memory CD4 and CD8 T cells are present in vivo of patients with CLL and that several leukemia cell–associated antigens/epitopes are recognized by the patients' immune system, indicating that whole leukemia cells might be of preference for vaccine development.

scholarly journals Selective dependence on IL-7 for antigen-specific CD8 T cell responses during airway influenza infection

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Abdalla Sheikh ◽  
Jennie Jackson ◽  
Hanjoo Brian Shim ◽  
Clement Yau ◽  
Jung Hee Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Mediastinal Lymph Node ◽  
Influenza Infection ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Deficient Mice

AbstractInterleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following influenza infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7Rα signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of influenza-specific CD8 T cells therein. We show that IL-7 plays a cell-intrinsic role in the accumulation of NP366–374 and PA224–233-specific CD8 T cells in the lymph node. We also found that IL-7 shapes terminal differentiation, degranulation and cytokine production to a greater extent in PA224–233-specific than NP366–374-specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of therapeutics that are currently available.

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