Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1667-1677 ◽  
Author(s):  
Judy Lieberman ◽  
Premlata Shankar ◽  
N. Manjunath ◽  
Jan Andersson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Short Term Exposure ◽  
Infected Cells ◽  
Hiv 1

Abstract CD8 T cells play an important role in protection and control of HIV-1 by direct cytolysis of infected cells and by suppression of viral replication by secreted factors. However, although HIV-1–infected individuals have a high frequency of HIV-1–specific CD8 T cells, viral reservoirs persist and progressive immunodeficiency generally ensues in the absence of continuous potent antiviral drugs. Freshly isolated HIV-specific CD8 T cells are often unable to lyse HIV-1–infected cells. Maturation into competent cytotoxic T lymphocytes may be blocked during the initial encounter with antigen because of defects in antigen presentation by interdigitating dendritic cells or HIV-infected macrophages. The molecular basis for impaired function is multifactorial, due to incomplete T-cell signaling and activation (in part related to CD3ζ and CD28 down-modulation), reduced perforin expression, and inefficient trafficking of HIV-specific CD8 T cells to lymphoid sites of infection. CD8 T-cell dysfunction can partially be corrected in vitro with short-term exposure to interleukin 2, suggesting that impaired HIV-specific CD4 T helper function may play a significant causal or exacerbating role. Functional defects are qualitatively different and more severe with advanced disease, when interferon γ production also becomes compromised.

scholarly journals Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

2008 ◽  
Vol 2 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Naveed Gulzar ◽  
Sowyma Balasubramanian ◽  
Greg Harris ◽  
Jaime Sanchez-Dardon ◽  
Karen F.T. Copeland
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Proliferative Response ◽  
Cell Infection ◽  
Cellular Target ◽  
Potential Reservoir ◽  
Infected Cells ◽  
Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

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 Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6351-6360 ◽  
Author(s):  
Jorge R. Almeida ◽  
Delphine Sauce ◽  
David A. Price ◽  
Laura Papagno ◽  
So Youn Shin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
Basic Knowledge ◽  
Suppressive Activity ◽  
Antiviral Efficacy ◽  
Hiv 1

Abstract CD8+ T cells are major players in the immune response against HIV. However, recent failures in the development of T cell–based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell–mediated efficacy. CD8+ T cells from HIV-1–infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8+ T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8+ T cells from infected donors. We report that attributes of CD8+ T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8+ T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8+ T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy.

scholarly journals T cell-mediated eradication of murine metastatic melanoma induced by targeted interleukin 2 therapy.

1996 ◽  
Vol 183 (5) ◽  
pp. 2361-2366 ◽  
Author(s):  
J C Becker ◽  
J D Pancook ◽  
S D Gillies ◽  
K Furukawa ◽  
R A Reisfeld
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Tumor Model ◽  
Melanoma Metastases ◽  
Tumor Eradication

Induction of a T-cell mediated antitumor response is the ultimate goal for tumor immunotherapy. We demonstrate here that antibody-targeted IL2 therapy is effective against established pulmonary and hepatic melanoma metastases in a syngeneic murine tumor model. The effector mechanisms involved in this tumor eradication are not dependent on NK cells, since the therapeutic effect of antibody-IL2 fusion protein was not altered in NK cell-deficient mice. In contrast, T cells are essential for the observed antitumor effect, since therapy with antibody IL2 fusion proteins is unable to induce tumor eradication in T cell-deficient SCID mice. In vivo depletion studies characterized the essential effector cell population further as CD8 + T cells. Such CD8 + T cells, isolated from tumor bearing mice after antibody-directed IL2 therapy, exerted a MHC class I-restricted cytotoxicity against the same tumor in vitro. These data demonstrate the ability of antibody-targeted IL2 delivery to induce a T cell-dependent host immune response that is capable of eradicating established melanoma metastases in clinically relevant organs.

scholarly journals Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Enrico Palermo ◽  
Chiara Acchioni ◽  
Daniele Di Carlo ◽  
Alessandra Zevini ◽  
Michela Muscolini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Histone Deacetylase ◽  
Innate Immune ◽  
Viral Reservoir ◽  
Hiv Eradication ◽  
Shock And Kill ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The “shock-and-kill” strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro. Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4+ central memory T (TCM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4+ T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells. IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (so-called “shock-and-kill” strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.

scholarly journals Interleukin-15 Triggers Activation and Growth of the CD8 T-Cell Pool in Extravascular Tissues of Patients With Acquired Immunodeficiency Syndrome

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 1115-1123 ◽  
Author(s):  
Carlo Agostini ◽  
Livio Trentin ◽  
Rosaria Sancetta ◽  
Monica Facco ◽  
Cristina Tassinari ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd8 T Cells ◽  
Biological Activities ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
Tissue Growth ◽  
Activation Markers ◽  
Accessory Function

Abstract The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the β and γ chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15Rα. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2Rβ/IL-2Rγ complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-α upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti–IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell–mediated immune response.

Targeting Lymphocyte Activation Gene 3 to Reverse T-Lymphocyte Dysfunction and Improve Survival in Murine Polymicrobial Sepsis

2020 ◽  
Vol 222 (6) ◽  
pp. 1051-1061
Author(s):  
Jing-sheng Lou ◽  
Jia-feng Wang ◽  
Miao-miao Fei ◽  
Yan Zhang ◽  
Jun Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Interleukin 2 ◽  
Lymphocyte Activation ◽  
Interferon Γ ◽  
T Cell Apoptosis ◽  
Cytokine Levels ◽  
Lymphocyte Activation Gene

Abstract Background Lymphocyte activation gene 3 (LAG-3) is one of the immune checkpoint molecules, negatively regulating the T-cell reactions. The present study investigated the role of LAG-3 in sepsis-induced T-lymphocyte disability. Methods Mice sepsis was induced by cecal ligation and puncture (CLP). LAG-3 expression on some immune cells were detected 24 hours after CLP. LAG-3 knockout and anti–LAG-3 antibody were applied to investigate the effects on the survival, bacterial clearance. Cytokine levels, T-cell counts, and the presence of apoptosis (in blood, spleen, and thymus) were also determined. In vitro T-cell apoptosis, interferon γ secretion, and proliferation were measured. The expression of interleukin 2 receptor on T cells was also determined after CLP. Results LAG-3 was up-regulated on CD4+/CD8+ T, CD19+ B, natural killer, CD4+CD25+ regulatory T cells and dendritic cells. Both LAG-3 knockout and anti–LAG-3 antibody had a positive effect on survival and on blood or peritoneal bacterial clearance in mice undergoing CLP. Cytokine levels and T-cell apoptosis decreased in anti–LAG-3 antibody–treated mice. Induced T-cell apoptosis decreased, whereas interferon γ secretion and proliferation were improved by anti–LAG-3 antibody in vitro. Interleukin 2 receptor was up-regulated on T cells in both wild-type and LAG-3–knockout mice undergoing CLP. Conclusions LAG-3 knockout or anti–LAG-3 antibody blockade protected mice undergoing CLP from sepsis-associated immunodysfunction and may be a new target for the treatment.

scholarly journals Human Immunodeficiency Virus Type 1 (HIV-1) Antigen Secretion by Latently Infected Resting CD4+ T Lymphocytes from HIV-1-Infected Individuals

2004 ◽  
Vol 78 (19) ◽  
pp. 10536-10542 ◽  
Author(s):  
Jean-Michel Fondere ◽  
Gael Petitjean ◽  
Marie-France Huguet ◽  
Sharon Lynn Salhi ◽  
Vincent Baillat ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In resting CD4+ T lymphocytes harboring human immunodeficiency virus type 1 (HIV-1), replication-competent virus persists in patients responding to highly active antiretroviral therapy (HAART). This small latent reservoir represents between 103 and 107 cells per patient. However, the efficiency of HIV-1 DNA-positive resting CD4+ T cells in converting to HIV-1-antigen-secreting cells (HIV-1-Ag-SCs) after in vitro CD4+-T-cell polyclonal stimulation has not been satisfactorily evaluated. By using an HIV-1-antigen enzyme-linked immunospot assay, 8 HIV-1-Ag-SCs per 106 CD4+ resting T cells were quantified in 25 patients with a plasma viral load of <20 copies/ml, whereas 379 were enumerated in 10 viremic patients. In parallel, 369 and 1,238 copies of HIV-1 DNA per 106 CD4+ T cells were enumerated in the two groups of patients, respectively. Only a minority of latently HIV-1 DNA-infected CD4+ T cells could be stimulated in vitro to become HIV-1-Ag-SCs, particularly in aviremic patients. The difference between the number of HIV-1 immunospots in viremic versus aviremic patients could be explained by HIV-1 unintegrated viral DNA that gave additional HIV-1-Ag-SCs after in vitro CD4+-T-cell polyclonal stimulation. The ELISPOT approach to targeting the HIV-1-Ag-SCs could be a useful method for identifying latently HIV-1-infected CD4+ T cells carrying replication-competent HIV-1 in patients responding to HAART.

scholarly journals Shared reactivity of Vδ2neg γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells

2005 ◽  
Vol 201 (10) ◽  
pp. 1567-1578 ◽  
Author(s):  
Franck Halary ◽  
Vincent Pitard ◽  
Dorota Dlubek ◽  
Roman Krzysiek ◽  
Henri de la Salle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Kidney Transplant Recipients ◽  
T Cell Clones ◽  
Cell Clones ◽  
Infected Cells

Long-lasting expansion of Vδ2neg γδ T cells is a hallmark of cytomegalovirus (CMV) infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, we generated γδ T cell clones from several transplanted patients. Numerous patient Vδ1+, Vδ3+, and Vδ5+ γδ T cell clones expressing diverse Vγ chains, but not control Vγ9Vδ2+ T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of tumor necrosis factor-α. Vδ2neg γδ T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required T cell receptor engagement, but did not involve major histocompatibility complex class I molecules or NKG2D. Vδ2neg γδ T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific Vδ2neg γδ T lymphocytes were found among patients' γδ T cells. In conclusion, Vδ2neg γδ T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from Vγ9Vδ2+ T cells.

scholarly journals Delivery of IL-2 to the T Cell Surface Through Phosphatidylserine Permits Robust Expansion of CD8 T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Alana MacDonald ◽  
Brandon Lam ◽  
John Lin ◽  
Louise Ferrall ◽  
Yu Jui Kung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Annexin V ◽  
Cell Immunity

The phospholipid phosphatidylserine (PS) is naturally maintained on the cytoplasmic side of the plasma membrane. Independent of apoptosis, PS is redistributed to the surface of CD8 T cells in response to TCR-mediated activation. Annexin V (AnnV) is a protein known to bind PS with high affinity and has been effectively utilized to anchor antigen to the surface of CD8 T cells. To expand these studies, we aimed to exploit TCR activation driven PS exposure as a target to deliver cytokine, namely interleukin-2 (IL-2), to the surface of CD8 T cells. This was accomplished using a novel chimeric fusion protein of annexin V and interleukin 2 (AnnV-IL2). In vitro analysis revealed that AnnV-IL2 is able to specifically bind PS on the T cell surface following TCR stimulation. Consequently, AnnV-IL2 proved to be significantly more effective at enhancing T cell activation compared to recombinant IL-2. In vivo, AnnV-IL2 promotes robust expansion of antigen-specific cells capable of interferon gamma (IFNγ) production when administered following peptide vaccination. Importantly, upon antigen rechallenge, AnnV-IL2 treatment mice demonstrated a stronger secondary expansion, indicating durability of AnnV-IL2 mediated responses. Our data supports the use of AnnV-IL2 to modulate antigen-specific T cell immunity and demonstrates that the PS-AnnV axis is a feasible mechanism to target diverse cargo to CD8 T cells.

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