Identification of a Shared CD4+ and CD8+ T Cell Epitope within Human Neutrophil Elastase for Peptide Vaccination in HLA-A02 Negative Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1803-1803
Author(s):  
Quan Le ◽  
J. Joseph Melenhorst ◽  
Rachel E. Hewitt ◽  
Nancy Hensel ◽  
A. John Barrett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cytotoxic T Cells ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Surface Expression ◽  
Human Neutrophil Elastase ◽  
Peptide Treatment

Abstract Human Neutrophil Elastase (HNE) is aberrantly expressed by myeloid leukemia cells and contains the antigenic PR1 peptide sequence inducing HLA-A*0201 restricted cytotoxic T cells (CTL) against leukemic cells. Our previous studies demonstrated that full length HNE protein can induce both CD4+ and CD8+ T cell responses in healthy individuals including HLA- A*0201 negative individuals, indicating an immunogenic potential of HNE beyond the PR1 peptide (Fujiwara H et al Blood 2004). To identify new HNE epitopes, a peptide matrix consisting of 15mers overlapping by 11 amino acids spanning HNE was screened using peripheral blood mononuclear cells (PBMC) from patients with acute myeloid leukemias (AML). Peptide candidates predicted using syfpeithi predictive algorithms were evaluated by measuring responses to candidate epitopes. We found a novel HNE peptide E17 (HNE: 65–80), recognized by both CD4+ and CD8+ T cells in an HLA-A (11, 31) patient with AML. E17 induced significant proliferation of CD4+ T cells 3.2X and CD8+ T cells 4.6X above background, as measured by CFSE flow cytometry-based proliferation assay. E17 induced IFN-g expression in CD4+ T cells 7.4X and in CD8+ T cells 2.5X above background in flow cytometric assay (see figure). E17 (HNE: 65–80) peptide induced IFN-g mRNA expression 3 hours after peptide treatment of PBMC, as measured by quantitative Real-Time RT-PCR assay. Finally, we showed by flow cytometry that E17 induced cell surface expression of CD137 in CD4+ T cells 2.4X and CD8+ T cells 1.7X above background 8 hours after peptide treatment of the cells. Antigen-driven surface expression of CD137 was used to isolate peptide E17 antigen-specific T cells, for further in vitro expansion and characterization of the T cell response. Thus we have identified a shared CD4+ and CD8+ T cell epitope in HNE, inducing the proliferation and effecter functions in CD4+ and CD8+ T cells. Since this epitope (HNE: 65–80) recruits both helper and cytotoxic T cells, it is well suited for peptide vaccine applications. This study provides the rationale for using the novel E17 (HNE: 65–80) peptide to vaccinate patients with myeloid leukemias. Figure Figure

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.

BK Polyomavirus–Specific CD8 T-Cell Expansion In Vitro Using 27mer Peptide Antigens for Developing Adoptive T-Cell Transfer and Vaccination

2020 ◽  
Author(s):  
Maud Wilhelm ◽  
Amandeep Kaur ◽  
Marion Wernli ◽  
Hans H Hirsch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Kidney Transplant ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Bk Polyomavirus

Abstract Background BK polyomavirus (BKPyV) remains a significant cause of premature kidney transplant failure. In the absence of effective antivirals, current treatments rely on reducing immunosuppression to regain immune control over BKPyV replication. Increasing BKPyV-specific CD8 T cells correlate with clearance of BKPyV DNAemia in kidney transplant patients. We characterized a novel approach for expanding BKPyV-specific CD8 T cells in vitro using 27mer-long synthetic BKPyV peptides, different types of antigen-presenting cells, and CD4 T cells. Methods Langerhans cells and immature or mature monocyte-derived dendritic cells (Mo-DCs) were generated from peripheral blood mononuclear cells of healthy blood donors, pulsed with synthetic peptide pools consisting of 36 overlapping 27mers (27mP) or 180 15mers (15mP). BKPyV-specific CD8 T-cell responses were assessed by cytokine release assays using 15mP or immunodominant 9mers. Results BKPyV-specific CD8 T cells expanded using 27mP and required mature Mo-DCs (P = .0312) and CD4 T cells (P = .0156) for highest responses. The resulting BKPyV-specific CD8 T cells proliferated, secreted multiple cytokines including interferon γ and tumor necrosis factor α, and were functional (CD107a+/PD1–) and cytotoxic. Conclusions Synthetic 27mP permit expanding BKPyV-specific CD8 T-cell responses when pulsing mature Mo-DCs in presence of CD4 T cells, suggesting novel and safe approaches to vaccination and adoptive T-cell therapies for patients before and after kidney transplantation.

scholarly journals Pathogenic Potential of Borna Disease Virus Lacking the Immunodominant CD8 T-Cell Epitope

2007 ◽  
Vol 81 (20) ◽  
pp. 11187-11194 ◽  
Author(s):  
Kirsten Richter ◽  
Karen Baur ◽  
Andreas Ackermann ◽  
Urs Schneider ◽  
Jürgen Hausmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Neurological Disease ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Epitope ◽  
Wild Type ◽  
Antiviral T Cells ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a highly neurotropic, noncytolytic virus. Experimentally infected B10.BR mice remain healthy unless specific antiviral T cells that infiltrate the infected brain are triggered by immunization. In contrast, infected MRL mice spontaneously mount an antiviral T-cell response that can result in meningoencephalitis and neurological disease. The antiviral T cells may, alternatively, eliminate the virus without inducing disease if they are present in sufficient numbers before the virus replicates to high titers. Since the immune response of H-2k mice is directed mainly against the epitope TELEISSI located in the viral nucleoprotein N, we generated BDV mutants that feature TQLEISSI in place of TELEISSI. We show that adoptive transfer of BDV N-specific CD8 T cells induced neurological disease in B10.BR mice persistently infected with wild-type BDV but not with the mutant virus expressing TQLEISSI. Surprisingly, the mutant virus replicated less well in adult MRL wild-type mice than in mutant mice lacking mature CD8 T cells. Furthermore, when MRL mice were infected with the TQLEISSI-expressing BDV mutant as newborns, neurological disease was observed, although at a lower rate and with slower kinetics than in mice infected with wild-type virus. These results confirm that TELEISSI is the major CD8 T-cell epitope in H-2k mice and suggest that unidentified minor epitopes are present in the BDV proteome which are recognized rather efficiently by antiviral T cells if the dominant epitope is absent.

Universal CD137 Expression upon Activation Allows Efficient Isolation of a Broad Repertoire of Virus-Specific CD8+ and CD4+ T Cells for Adoptive Immunotherapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2222-2222
Author(s):  
Maarten L. Zandvliet ◽  
J.H. Frederik Falkenburg ◽  
Inge Jedema ◽  
Roelof Willemze ◽  
Henk-Jan Guchelaar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Cell Populations ◽  
T Cell Lines ◽  
Kinetics Of ◽  
Ifng Production

Abstract Reactivation of adenovirus (ADV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can cause serious morbidity and mortality during the prolonged period of immune deficiency following allogeneic stem cell transplantation. It has been shown that adoptive transfer of donor-derived virus-specific T cells can be a successful strategy to control viral reactivation. To provide safe and effective anti-viral immunotherapy, we aimed to generate combined CD8+ and CD4+ T cell lines with high specificity for a broad range of viral epitopes. Isolation by the IFNg capture assay of virus-specific T cells that produce IFNg upon activation allows the generation of highly specific T cell lines without the need for extensive culture. However, it has been recently shown that specific upregulation of the co-stimulatory molecule CD137 upon antigen-specific activation of CD8+ and CD4+ T cells can also be used for isolation. We therefore analyzed IFNg production and CD137 expression by CD8+ and CD4+ T cells upon incubation of peripheral blood mononuclear cells (PBMC) from seropositive donors with peptides corresponding to 17 defined MHC class I restricted minimal epitopes from 10 different ADV, CMV, EBV and influenza (FLU) proteins, and 15-mer or 30-mer peptides containing MHC class II restricted epitopes from CMV pp65 or ADV hexon. Using tetramer and intracellular IFNg staining we first determined the fraction of CD8+ T cells that produced IFNg upon activation with the minimal epitopes. Specific IFNg production was observed for 58–100% of tetramer+ CD8+ T cells specific for CMV pp65 (n=6), and 83% for FLU (n=1), but only 18–58% for CMV pp50 (n=3) or IE-1 (n=3), 4–91% for EBV latent (n=3) and lytic (n=3) epitopes, and 41–63% for ADV hexon (n=2). In contrast to the variation in the fraction of IFNg-producing cells, we observed homogeneous upregulation of CD137 by the virus-specific tetramer+ T cell populations upon activation. In 2 cases where no CD137 expression by tetramer+ T cells could be detected, no IFNg production was observed either. These data suggest that the majority of CD8+ T cells specific for CMV pp65 or FLU can be isolated on basis of IFNg production, but only part of CD8+ T cell populations specific for other viral proteins, while complete virus-specific CD8+ T cell populations may be isolated on basis of CD137 expression. Activation of CD4+ T cells specific for CMV pp65 or ADV hexon with 15-mer or 30-mer peptides induced both specific IFNg production and CD137 expression. To investigate whether multiple virus-specific T cell populations could be isolated simultaneously, we next determined the kinetics of IFNg production after activation with defined MHC class I epitopes or peptides containing MHC class II epitopes. CMV- and EBV-specific CD8+ T cells and CMV-specific CD4+ T cells showed a rapid induction of IFNg production, which peaked after 4 hours and decreased thereafter. In contrast, ADV- and FLU-specific CD8+ T cells and ADV-specific CD4+ T cells, predominantly having a more early differentiation phenotype (CD27+CD28+) compared to CMV- and EBV-specific T cells, showed peak IFNg production after 8 hours that continued for more than 48 hours. This difference in phenotype and IFNg kinetics may suggest that the persistent and frequent presentation of CMV and EBV epitopes in vivo, in contrast to an intermittent exposure to ADV and FLU epitopes, drives differentiation and shapes the kinetics of the IFNg response of specific T cells. Kinetic analysis of CD137 expression showed uniform upregulation by virus-specific CD8+ T cell populations from day 1 to day 4 after activation, which peaked at day 2, suggesting that this may be the optimal time point for CD137-based isolation. In a limited number of experiments, virus-specific CD8+ and CD4+ T cells could be isolated based on CD137 expression within the same timeframe. These data indicate that virus-specific T cell populations can be more efficiently isolated at one time point on basis of CD137 expression than on basis of IFNg production, due to differences in IFNg kinetics. In conclusion, this study shows that T cell lines generated by CD137 isolation may comprise a significant number of virus-specific T cells which do not produce IFNg, but may have other effector functions. Furthermore, CD137-based enrichment may be more robust and allows the efficient simultaneous isolation of multiple virus-specific T cell populations due to uniform kinetics of CD137 expression.

Perforin Is Important For Both CD4+ and CD8+ T Cell-Mediated Graft-Versus-Tumor Effect But Plays Differential Roles In CD4+ and CD8+ T Cell Expansion After Allogeneic Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3255-3255
Author(s):  
Nicholas Leigh ◽  
Guanglin Bian ◽  
Wei Du ◽  
George L. Chen ◽  
Hong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
T Cell Expansion ◽  
Time Point

Abstract Graft versus tumor (GVT) effect is the desired and integral outcome for successful allogeneic bone marrow transplantation (allo-BMT) for cancer patients. This effect is dependent on T cell mediated recognition and elimination of residual host tumor cells present after allo-BMT. T cell killing is mediated primarily via three pathways: perforin/granzymes, Fas/FasL, and cytotoxic cytokines. Recent work from our lab has revealed a detrimental role for granzyme B (GzmB) in GVT effect due to its role in activation induced cell death (AICD) of CD8+ T cells. As a result, GzmB-/- CD8+ T cells exhibited higher expansion after allo-BMT and subsequently provided better tumor control. Our current study sought to determine the role of perforin (Prf1) in GVT effect mediated by both CD4+ and CD8+ T cells. Using the MHC-mismatched C57BL/6 (H-2b) to BALB/c (H-2d) allo-BMT model, we first confirmed previous findings that when transplanting CD8+ T cells along with T cell depleted (TCD) BM cells, donor CD8+ T cells require Prf1 to mediate GVT effect against allogeneic A20 lymphoma (Fig 1A, Prf1-/- (n=4) vs WT (n=4), *P<0.05). In addition, our data suggest that Prf1 is also required for CD4+ T cells to effectively mediate GVT effect against A20, as transplant with Prf1-/- CD4+CD25- T cells does not control tumor growth as well as WT controls (Fig 1B). Our previous work showed that GzmB deficiency allows for less AICD and subsequently more CD8+ T cell expansion. New data now show a similar effect for Prf1 in CD8+ T cell accumulation, as Prf1-/- CD8+ T cells outcompete WT CD8+ T cells (CD45.1+) when these two genotypes are mixed in equal numbers and transplanted into tumor bearing BALB/c mice (n=5/time point, *P=0.02 day 9)(Fig 1C). This competitive advantage was due to less AICD in the Prf1-/- CD8+ T cells. However, Prf1 appears to be required for efficient GVT activity, because the higher number of Prf1-/- CD8+ T cells are still less capable than WT counterparts in controlling tumor growth. We next tested the effect of Prf1 in AICD in CD4+CD25- T cells, and again co-transplanted WT CD45.1+ and Prf1-/- CD4+CD25- T cells into tumor bearing mice for a competition assay. Unexpectedly, WT CD4+CD25- T cells accumulate to significantly higher numbers when in direct competition with Prf1-/- CD4+CD25- T cells (n=4/time point, **,P<0.01)(Fig 1D). When we measured apoptotic cells with Annexin V staining, we found that WT CD4+CD25- T cells still had significantly more AICD (Prf1-/- 38.3 ± 4.2% vs. WT 48.1 ± 5.1%, P<0.01 on day 7 post-BMT; Prf1-/- 12.7 ± 1.0% vs. WT 18.1 ± 3.4%, P<0.03 on day 9 post-BMT). This result suggests that while Prf1 has an important role in AICD, it may also play a role in another feature of CD4+ T cell biology. We then explored the hypothesis that may Prf1 promote CD4+ T cell proliferation by evaluating Hoescht staining on day 9 post-BMT. Preliminary results suggest that Prf1 may enhance T cell proliferation, as Prf1-/- CD4+ T cells have less actively dividing cells at this time point. Therefore, Prf1 appears to have a surprising role after allo-BMT in sustaining T cell expansion for CD4+ T cells, but not for CD8+ T cells. Another factor influencing GVT effect may be T cell phenotype. Our previous work with CD8+ T cells suggests that more effector memory (CD62LLOWCD44HIGH) T cells accumulate in the absence of GzmB, and that GzmB-/- CD8+ T cells exhibited higher GVT activity than WT controls. We now found that while Prf1-/- CD4+ T cells also skewed towards the effector memory phenotype (CD62LLOWCD44HIGH), loss of Prf1 still reduced the ability of CD4+ T cells to control tumor growth in this model of allo-BMT. In summary, our results suggest that Prf1 plays an important role in GVT responses mediated not only by CD8+ T cells but also by CD4+ T cells, which were shown in previous literature to mainly utilize Fas ligand and cytokine systems to mediate GVT activity. In addition, Prf1 can cause AICD to both CD4+ and CD8+ T cells after allo-BMT. While Prf1-induced AICD reduces CD8+ T cell expansion, Prf1 appears to play a previously unrecognized role enhancing CD4+ T cell proliferation via an unidentified mechanism. Disclosures: No relevant conflicts of interest to declare.

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 195-202 ◽  
Author(s):  
Masaki Tateyama ◽  
Naoki Oyaizu ◽  
Thomas W. McCloskey ◽  
Soe Than ◽  
Savita Pahwa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cross Linking ◽  
Induced Apoptosis ◽  
Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

scholarly journals Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2400-2410 ◽  
Author(s):  
Yoshimi Enose-Akahata ◽  
Unsong Oh ◽  
Christian Grant ◽  
Steven Jacobson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Spastic Paraparesis ◽  
Cd8 T Cell ◽  
Mononuclear Phagocytes ◽  
Type I ◽  
Human T Cell ◽  
Ifn Γ

AbstractCD8+ T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8+ T-cell dysfunction (degranulation and IFN-γ production) and have demonstrated that CD8+ T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-γ in ex vivo unstimulated culture. CD8+ T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer+ cells, but not in CMV pp65 tetramer+ cells. Interestingly, degranulation and IFN-γ production in CD8+ T cells was induced by coculture with autologous CD14+ cells, but not CD4+ T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14+ cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-γ production in infected patients, was enhanced on surface of CD14+ cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8+ T-cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14+ cells in HAM/TSP patients. Despite lower viral expression than in CD4+ T cells, HTLV-I–infected or –activated CD14+ cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients.

scholarly journals c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation

2002 ◽  
Vol 195 (7) ◽  
pp. 811-823 ◽  
Author(s):  
Dietrich Conze ◽  
Troy Krahl ◽  
Norman Kennedy ◽  
Linda Weiss ◽  
Joanne Lumsden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Surface Expression ◽  
Chain Gene ◽  
Α Chain

The c-Jun NH2-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8+ T cells. Unlike CD4+ T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8+ T cells. In contrast, JNK1-deficient CD8+ T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor α chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8+ T cells can account for the impaired IL-2 receptor α chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8+ T cell activation and these roles differ from those in CD4+ T cells.

scholarly journals Organ- and Disease-Stage-Specific Regulation of Toxoplasma gondii-Specific CD8-T-Cell Responses by CD4 T Cells

2006 ◽  
Vol 74 (10) ◽  
pp. 5790-5801 ◽  
Author(s):  
Sonja Lütjen ◽  
Sabine Soltek ◽  
Simona Virna ◽  
Martina Deckert ◽  
Dirk Schlüter
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cd8 T Cells ◽  
Functional Activity ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Ifn Γ

ABSTRACT Toxoplasma gondii induces a persistent central nervous system infection, which may be lethally reactivated in AIDS patients with low CD4 T-cell numbers. To analyze the role of CD4 T cells for the regulation of parasite-specific CD8 T cells, mice were infected with transgenic T. gondii expressing the CD8 T-cell antigen β-galactosidase (β-Gal). Depletion of CD4 T cells prior to infection did not affect frequencies of β-Gal876-884-specific (consisting of residues 876 to 884 of β-Gal) CD8 T cells but resulted in a pronounced reduction of intracerebral β-Gal-specific gamma interferon (IFN-γ)-producing and cytolytic CD8 T cells. After cessation of anti-CD4 treatment a normal T. gondii-specific CD4 T-cell response developed, but IFN-γ production of intracerebral β-Gal-specific CD8 T cells remained impaired. The important supportive role of CD4 T cells for the optimal functional activity of intracerebral CD8 T cells was also observed in mice that had been depleted of CD4 T cells during chronic toxoplasmosis. Reinfection of chronically infected mice that had been depleted of CD4 T cells during either the acute or chronic stage of infection resulted in an enhanced proliferation of β-Gal-specific IFN-γ-producing splenic CD8 T cells. However, reinfection of chronically infected mice that had been depleted of CD4 T cells in the acute stage of infection did not reverse the impaired IFN-γ production of intracerebral CD8 T cells. Collectively, these findings illustrate that CD4 T cells are not required for the induction and maintenance of parasite-specific CD8 T cells but, depending on the stage of infection, the infected organ and parasite challenge infection regulate the functional activity of intracerebral CD8 T cells.

scholarly journals CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity

2021 ◽  
Vol 9 ◽  
Author(s):  
Pedro Briceño ◽  
Elizabeth Rivas-Yañez ◽  
Mariana V. Rosemblatt ◽  
Brian Parra-Tello ◽  
Paula Farías ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Tumor Burden ◽  
Effector Cells ◽  
Cd73 Expression ◽  
Metabolic Fitness

CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness.

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