HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines

Adult T-cell leukemia (ATL) patients and human T-cell leukemia virus-1 (HTLV-1) infected individuals succumb to opportunistic infections. Cell mediated immunity is impaired, yet the mechanism of this impairment has remained elusive. The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the viral DNA and is constitutively expressed in infected cells and ATL cells. To test the hypothesis that HBZ contributes to HTLV-1–associated immunodeficiency, we challenged transgenic mice that express the HBZ gene in CD4 T cells (HBZ-Tg mice) with herpes simplex virus type 2 or Listeria monocytogenes, and evaluated cellular immunity to these pathogens. HBZ-Tg mice were more vulnerable to both infections than non-Tg mice. The acquired immune response phase was specifically suppressed, indicating that cellular immunity was impaired in HBZ-Tg mice. In particular, production of IFN-γ by CD4 T cells was suppressed in HBZ-Tg mice. HBZ suppressed transcription from the IFN-γ gene promoter in a CD4 T cell–intrinsic manner by inhibiting nuclear factor of activated T cells and the activator protein 1 signaling pathway. This study shows that HBZ inhibits CD4 T-cell responses by directly interfering with the host cell-signaling pathway, resulting in impaired cell-mediated immunity in vivo.

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The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals

Blood ◽

10.1182/blood-2010-09-305805 ◽

2011 ◽

Vol 117 (13) ◽

pp. 3609-3612 ◽

Cited By ~ 22

Author(s):

Andrea K. Kress ◽

Martina Kalmer ◽

Aileen G. Rowan ◽

Ralph Grassmann ◽

Bernhard Fleckenstein

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Marker ◽

Cd4 T Cells ◽

Initial Step ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Viral Oncoprotein ◽

Adult T Cell Leukemia ◽

Human T Cell

AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

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HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity

Journal of Experimental Medicine ◽

10.1084/jem.20031598 ◽

2003 ◽

Vol 198 (12) ◽

pp. 1909-1922 ◽

Cited By ~ 339

Author(s):

Souheil-Antoine Younes ◽

Bader Yassine-Diab ◽

Alain R. Dumont ◽

Mohamed-Rachid Boulassel ◽

Zvi Grossman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Memory Cells ◽

Cell Responses ◽

Specific Memory ◽

Ifn Γ ◽

Memory Cd4 T Cells

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-γ–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-γ only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-γ only–producing cells that lack self-renewal capacity.

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CD4 T-Cell-Mediated Demyelination Is Increased in the Absence of Gamma Interferon in Mice Infected with Mouse Hepatitis Virus

Journal of Virology ◽

10.1128/jvi.76.14.7329-7333.2002 ◽

2002 ◽

Vol 76 (14) ◽

pp. 7329-7333 ◽

Cited By ~ 42

Author(s):

Lecia Pewe ◽

Jodie Haring ◽

Stanley Perlman

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Hepatitis Virus ◽

Mouse Hepatitis Virus ◽

Gamma Interferon ◽

Cd4 T Cell ◽

Immune Mediated ◽

Donor Cells ◽

Ifn Γ

ABSTRACT Mice infected with the murine coronavirus, mouse hepatitis virus, strain JHM (MHV) develop an immune-mediated demyelinating encephalomyelitis. Adoptive transfer of MHV-immune splenocytes depleted of either CD4 or CD8 T cells to infected mice deficient in recombination activation gene 1 resulted in demyelination. We showed previously that the process of CD8 T-cell-mediated demyelination was strongly dependent on the expression of gamma interferon (IFN-γ) by donor cells. In this report, we show, in contrast, that demyelination and lymphocyte infiltration were increased in recipients of IFN-γ−/− CD4 T cells when compared to levels in mice receiving C57BL/6 CD4 T cells.

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Enteral Immunization with Attenuated Recombinant Listeria monocytogenes as a Live Vaccine Vector: Organ-Dependent Dynamics of CD4 T Lymphocytes Reactive to a Leishmania major Tracer Epitope

Infection and Immunity ◽

10.1128/iai.71.3.1083-1090.2003 ◽

2003 ◽

Vol 71 (3) ◽

pp. 1083-1090 ◽

Cited By ~ 12

Author(s):

Hélène Saklani-Jusforgues ◽

Elisabeth Fontan ◽

Neirouz Soussi ◽

Geneviève Milon ◽

Pierre L. Goossens

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

T Cell ◽

Cd4 T Cells ◽

Leishmania Major ◽

Cd4 T Cell ◽

Interleukin 4 ◽

Cell Immune Response ◽

Mesenteric Lymph Nodes ◽

Ifn Γ

ABSTRACT Listeria monocytogenes is considered as a potential live bacterial vector, particularly for the induction of CD8 T cells. The CD4 T-cell immune response triggered after enteral immunization of mice has not yet been thoroughly characterized. The dynamics of gamma interferon (IFN-γ)- and interleukin-4 (IL-4)-secreting CD4 T cells were analyzed after priming through intragastric delivery of an attenuated ΔactA recombinant L. monocytogenes strain expressing the Leishmania major LACK protein; a peptide of this protein, LACK158-173 peptide (pLACK), is a well-characterized CD4 T-cell target in BALB/c mice. Five compartments were monitored: Peyer's patches, mesenteric lymph nodes (MLN), spleen, liver, and blood. A single intragastric inoculation of ΔactA-LACK-LM in BALB/c mice led to colonization of the MLN and spleen at a significant level for at least 3 days. Efficient priming of IFN-γ-secreting pLACK-reactive CD4 T cells was observed in all tested compartments. Interestingly, IL-4-secreting pLACK-reactive CD4 T cells were detectable at day 6 or 7 only in blood and liver. The absence of translocation of viable bacteria through the intestinal epithelium after further ΔactA-LACK-LM inoculations was concomitant with the absence of an increase in the level of IFN-γ secreted by the MLN, blood, and splenic pLACK-reactive Th1 T cells, although the levels remained significantly above the basal level. No change in this population size was detected in the spleen. However, an increase in the number of intragastric inoculations had a clinical beneficial effect in L. major-infected BALB/c mice. L. monocytogenes thus presents the potential of an efficient vector for induction of CD4 T cells when administered by the enteral route.

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

Infection and Immunity ◽

10.1128/iai.00098-06 ◽

2006 ◽

Vol 74 (10) ◽

pp. 5790-5801 ◽

Cited By ~ 26

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.

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The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

Journal of Immunology Research ◽

10.1155/2021/6625855 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Kunlong Xiong ◽

Jinxia Niu ◽

Ruijuan Zheng ◽

Zhonghua Liu ◽

Yanzheng Song ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Cd4 T Cell ◽

Cell Frequency ◽

Tnf Α ◽

Ifn Γ

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.

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Cyclophosphamide Plus Allogeneic CD4+ T Cell Infusion Induces Anti-Lymphoma Immunity Despite Lack of Graft-Versus-Host Disease (GVHD) or Sustained Engraftment.

Blood ◽

10.1182/blood.v104.11.3063.3063 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3063-3063

Author(s):

Sanju Jalla ◽

Jie Wang ◽

Leo Luznik ◽

Ephraim J. Fuchs

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Tumor Immunity ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Leukemia ◽

B Cell Leukemia ◽

T Cell Help

Abstract Recent evidence suggests that tumor-bearing animals contain CD8+ T cells that can respond productively to a tumor vaccine, but that these T cells do not respond because of insufficient help from tumor-specific CD4+ T cells, which have either been inactivated or turned into anti-tumor suppressor T cells. We therefore devised a strategy to augment anti-tumor immunity by administering cyclophosphamide (Cy), to eliminate suppressor CD4+ T cells, followed by combining autologous tumor cell vaccination and infusion of partially MHC-mismatched, or haploidentical, CD4+ T cells as a source of T cell help for endogenous CD8+ T cells. Interestingly, the combination of Cy followed by haploidentical T cell infusion, with or without vaccine, induced potent systemic anti-tumor immunity resulting in cure of 40-50% of BALB/c mice harboring the A20 B cell leukemia/lymphoma. Depletion of CD8+ T cells from the infusate abrogated GVHD but did not compromise anti-tumor immunity. Allogeneic donor spleen cells that contained CD8+ T cells engrafted durably and caused lethal GVHD. In contrast, the combination of Cy plus CD8+ T cell-depleted spleen cell infusion induced only transient engraftment, peaking on day 7 and declining to undetectable levels by day 14. In the absence of Cy conditioning, allogeneic donor spleen cell infusions did not induce detectable chimerism beyond day 3. In summary, Cy plus allogeneic CD4+ T cell infusion induces potent anti-tumor immunity in a mouse model of B cell leukemia/lymphoma. Potential mechanisms of the therapeutic effect include direct tumor cytotoxicity by CD4+ T cells or allogeneic CD4+ T cell help for endogenous, tumor-specific CD8+ T cells.

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Efficient Induction of HTLV-1-Specific CTL Response by HTLV-1/HBc Chimeric Particle without Adjuvant as a Prophylactic for HTLV-1- Associated T-Cell Leukemia

Blood ◽

10.1182/blood.v112.11.84.84 ◽

2008 ◽

Vol 112 (11) ◽

pp. 84-84

Author(s):

Tomohiro Kozako ◽

Katsuhiko Fukada ◽

Shinya Hirata ◽

Michiko Harao ◽

Yasuharu Nishimura ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cellular Immunity ◽

Elispot Assay ◽

Target Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Epitope Peptide ◽

Intradermal Immunization ◽

Efficient Induction

Abstract Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell neoplasm that develops only after long-term chronic infection with human T-cell leukemia virus-1 (HTLV-1). HTLV-1-specific Cytotoxic T lymphocytes (CTL) play an important role in suppressing proliferation of HTLV-1-infected or transformed T cells in vitro. The development of ATLL in approximately 2% of persons chronically infected with HTLV-1 may suggest a specific immunegenetic background predisposing to CTL failure in a proportion of HTLV-1 carriers. On the other hand, virus like particle is demonstrated to induce stronger humoral, T helper and cytotoxic T-cell responses without adjuvant. As free synthetic peptides or proteins are usually poor immunogens, the hepatitis B core (HBc) particle is a potential target carrier protein to induce immunity without use of an adjuvant. In this study, we examined the efficient induction of HTLV-1-specific CD8+ T-cell response by HTLV-1/HBc chimeric particles inserting HLA-A*0201-restricted HTLV-1 Tax-epitope without adjuvant (Figure 1). The immunization of HLA-A*0201 transgenic mice with the chimeric particle induced antigen-specific IFN-□ reaction by ELISPOT assay, whereas epitope peptide only induced no reaction (Figure 2). HTLV-1/HLA tetramer assay detected induction of HTLV-1-specific CD8+ T-cells in both splenic and inguinal lymph node cells by HTLV-1/HBc chimera particles. Furthermore, upon exposure of these dendritic cells (DCs) to the chimeric particles, the expression of CD86 was increased in a dose-dependent manner. These results suggest that HTLV-1/HBc chimeric particles are capable of inducing strong cellular immune responses without adjuvant via effective maturation of DCs and are potentially useful as an effective vaccine carrier for the treatment of cancers and infectious diseases by varying the epitope peptide. Figure 1. Electronmicrographs of recombinant HTLV-1 Tax/HBc chimeric particles. Figure 1. Electronmicrographs of recombinant HTLV-1 Tax/HBc chimeric particles. Figure 2. Induction of cellular immunity by intradermal immunization with HTLV-1/HBc chimeric particle. Mice were immunized twice with recombinant HTLV-1/HBc chimeric particle, HTLV-1 peptide and HTLV-1 peptide + HBc particle. The number of IFN-□-producing cells was measured by ELISPOT assay. IFN-□ spots show the number of peptide-loaded target cells to peptide-unloaded target cells. *P<0.05, **P<0.01 vs PBS group. The experiments were performed in triplicate. Mean S.E. are shown in the results. Figure 2. Induction of cellular immunity by intradermal immunization with HTLV-1/HBc chimeric particle. Mice were immunized twice with recombinant HTLV-1/HBc chimeric particle, HTLV-1 peptide and HTLV-1 peptide + HBc particle. The number of IFN-□-producing cells was measured by ELISPOT assay. IFN-□ spots show the number of peptide-loaded target cells to peptide-unloaded target cells. *P<0.05, **P<0.01 vs PBS group. The experiments were performed in triplicate. Mean S.E. are shown in the results.

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Wilms Tumor Protein-1-Derived 9-Mer Peptide Induces CD4 T-Cell Responses in an HLA-DR Restricted Manner

Blood ◽

10.1182/blood.v120.21.4351.4351 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4351-4351

Author(s):

Shigeo Fuji ◽

Julia Fischer ◽

Markus Kapp ◽

Thomas G Bumm ◽

Hermann Einsele ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Responses ◽

Class Ii ◽

Hla Class Ii ◽

Cd4 T Cell ◽

Cell Responses ◽

Hla Dr ◽

Ifn Γ

Abstract Abstract 4351 Wilms‘ tumor protein-1 (WT1) is one of the most investigated tumor-associated antigens (TAA) in hematological malignancies. CD8 T-cell responses against several WT1-derived peptides have been characterized and are known to contribute to disease control after allogeneic hematopoietic stem cell transplantation (HSCT). Also the identification of human leukocyte antigen (HLA) class II-restricted CD4 T-cell epitopes from WT1 is a challenging task of T-cell-based cancer immunotherapy to improve the effectiveness of WT1 peptide vaccination. We found a highly immunogenic WT1 peptide composed of only 9 amino acids having the ability to induce IFN-γ secretion in CD4 T-cells in an HLA DR-restricted manner. This finding is of great interest as it was generally accepted that HLA class II binding peptides are composed of at least 12 amino acids being recognized by CD4 T-cells, whereas HLA class I binding peptides are composed of 8–11 amino acids being recognized by CD8 T-cells (Wang et al Mol. Immunol. 2002). However, both HLA class I and class II molecules bind to primary and secondary peptide anchor motifs covering the central 9–10 amino acids. Thus, considering this common structural basis for peptide binding there is a possibility that the WT1 9-mer peptide binds to HLA class II molecules, and induces CD4 T-cell responses. IFN-γ induction in response to several WT1 9-mer peptides was screened in 24 HLA-A*02:01 positive patients with acute myeloid leukemia or myelodysplastic syndrome after allogeneic HSCT. Responses to one WT1 9-mer peptide were exclusively detected in CD3+CD4+ T-cells of 2 patients after allogeneic HSCT, but not in CD3+CD4+ T-cells of their corresponding HSC donors. CD4+ T-cell responses to this WT1 9-mer peptide exhibited high levels of functional avidity, as IFN-γ induction was detected after stimulation with 100 ng peptide per mL. Peptide-induced IFN-γ production was confirmed with IFN-γ ELISPOT assays and the HLA restriction of the T-cell response was determined by HLA blocking antibodies. The reaction was significantly blocked by anti-pan HLA class II antibody (85 % reduction), but neither by pan-HLA class I nor by anti-HLA A2 antibody. To identify the subtype of HLA class II molecule, blocking assays with antibodies against HLA-DP, HLA-DR and HLA-DQ were performed. IFN-γ induction was completely abrogated by anti-HLA-DR antibody (99 % reduction) (fig 1, p value of unpaired student‘s t-test <0.0001 for the medium control vs anti-pan HLA class II antibody or anti-HLA-DR antibody, respectively). To test whether IFN-γ was exclusively induced in CD4 T cells, CD4 or CD8 T-cells were depleted from PBMC. Whereas CD8 T-cell depletion did not affect IFN-γ induction, CD4 T-cell depletion completely abrogated the WT1 9-mer peptide induced response (fig 2). CD4 T-cells responding to the WT1 9-mer peptide were indicated to be functional cytotoxic T-cells with an effector CD4 T-cell phenotype. Longitudinal analyses demonstrated the persistence and functionality of WT1 9-mer specific CD4 T-cells in PBMC of patients even at day 1368 after allogeneic HSCT. These data indicate for the first time that a TAA-derived 9-mer peptide can induce HLA class II-restricted CD4 T-cell responses. Vaccination with the characterized WT1 9-mer peptide can enhance the induction and maintenance of not only CD4 but also indirect CD8 T-cell responses. Considering that CD4 T-cells play an important role in tumor rejection, the possibility that other TAA-derived 9-mer peptides having the potential to induce CD4 T-cell responses should be explored in other settings of tumor immunology as well to improve vaccination strategies. Disclosures: No relevant conflicts of interest to declare.

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