Not All Tetramer Binding CD8+ T Cells Can Produce Cytokines and Chemokines Involved in the Effector Functions of Virus-Specific CD8+ T Lymphocytes in HIV-1 Infected Children

Major histocompatibility class I–peptide tetramer technology and simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys were used to clarify the distribution of acquired immunodeficiency syndrome virus-specific cytotoxic T lymphocytes (CTL) in secondary lymphoid organs and to assess the relationship between these CTL and the extent of viral replication in the various anatomic compartments. SIVmac Gag epitope-specific CD8+ T cells were evaluated in the spleen, bone marrow, tonsils, thymus, and 5 different lymph node compartments of 4 SIVmac-infected rhesus monkeys. The average percentage of CD8+ T lymphocytes that bound this tetramer in all the different lymph node compartments was similar to that in peripheral blood lymphocytes in individual monkeys. The percentage of CD8+ T cells that bound the tetramer in the thymus was uniformly low in the monkeys. However, the percentage of CD8+ T cells that bound the tetramer in bone marrow and spleen was consistently higher than that seen in lymph nodes and peripheral blood. The phenotypic profile of the tetramer-binding CD8+ T lymphocytes in the different lymphoid compartments was similar, showing a high expression of activation-associated adhesion molecules and a low level expression of naive T-cell–associated molecules. Surprisingly, no correlation was evident between the percentage of tetramer-binding CD8+ T lymphocytes and the magnitude of the cell-associated SIV RNA level in each lymphoid compartment of individual monkeys. These studies suggest that a dynamic process of trafficking may obscure the tendency of CTL to localize in particular regional lymph nodes or that some lymphoid organs may provide milieus that are particularly conducive to CTL expansion.

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Simian immunodeficiency virus-specific cytotoxic T lymphocytes and cell-associated viral RNA levels in distinct lymphoid compartments of SIVmac-infected rhesus monkeys

Blood ◽

10.1182/blood.v96.4.1474 ◽

2000 ◽

Vol 96 (4) ◽

pp. 1474-1479 ◽

Cited By ~ 36

Author(s):

Marcelo J. Kuroda ◽

Jörn E. Schmitz ◽

Aruna Seth ◽

Ronald S. Veazey ◽

Christine E. Nickerson ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Lymph Node ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Cd8 T Cells ◽

Rhesus Monkeys ◽

Cd8 T Lymphocytes ◽

Tetramer Binding ◽

Immunodeficiency Virus

Abstract Major histocompatibility class I–peptide tetramer technology and simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys were used to clarify the distribution of acquired immunodeficiency syndrome virus-specific cytotoxic T lymphocytes (CTL) in secondary lymphoid organs and to assess the relationship between these CTL and the extent of viral replication in the various anatomic compartments. SIVmac Gag epitope-specific CD8+ T cells were evaluated in the spleen, bone marrow, tonsils, thymus, and 5 different lymph node compartments of 4 SIVmac-infected rhesus monkeys. The average percentage of CD8+ T lymphocytes that bound this tetramer in all the different lymph node compartments was similar to that in peripheral blood lymphocytes in individual monkeys. The percentage of CD8+ T cells that bound the tetramer in the thymus was uniformly low in the monkeys. However, the percentage of CD8+ T cells that bound the tetramer in bone marrow and spleen was consistently higher than that seen in lymph nodes and peripheral blood. The phenotypic profile of the tetramer-binding CD8+ T lymphocytes in the different lymphoid compartments was similar, showing a high expression of activation-associated adhesion molecules and a low level expression of naive T-cell–associated molecules. Surprisingly, no correlation was evident between the percentage of tetramer-binding CD8+ T lymphocytes and the magnitude of the cell-associated SIV RNA level in each lymphoid compartment of individual monkeys. These studies suggest that a dynamic process of trafficking may obscure the tendency of CTL to localize in particular regional lymph nodes or that some lymphoid organs may provide milieus that are particularly conducive to CTL expansion.

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Productive Infection of Neonatal CD8+ T Lymphocytes by HIV-1

Journal of Experimental Medicine ◽

10.1084/jem.187.7.1139 ◽

1998 ◽

Vol 187 (7) ◽

pp. 1139-1144 ◽

Cited By ~ 68

Author(s):

Liang Peng Yang ◽

James L. Riley ◽

Richard G. Carroll ◽

Carl H. June ◽

James Hoxie ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

T Lymphocytes ◽

Hiv Infection ◽

Cd8 T Cells ◽

Productive Infection ◽

Target Cells ◽

Cd8 T Lymphocytes ◽

Hiv 1

CD8+ T lymphocytes confer significant but ultimately insufficient protection against HIV infection. Here we report that activated neonatal CD8+ T cells can be productively infected in vitro by macrophage-tropic (M-tropic) HIV-1 isolates, which are responsible for disease transmission, whereas they are resistant to T cell–tropic (T-tropic) HIV strains. Physiological activation of CD8-α/β+ CD4− T cell receptor–α/β+ neonatal T cells, including activation by allogeneic dendritic cells, induces the accumulation of CD4 messenger RNA and the expression of CD4 Ag on the cell surface. The large majority of anti-CD3/B7.1–activated cord blood CD8+ T cells coexpress CD4, the primary HIV receptor, as well as CCR5 and CXCR4, the coreceptors used by M- and T-tropic HIV-1 strains, respectively, to enter target cells. These findings are relevant to the rapid progression of neonatal HIV infection. Infection of primary HIV-specific CD8+ T cells may compromise their survival and thus significantly contribute to the failure of the immune system to control the infection. Furthermore, these results indicate a previously unsuspected level of plasticity in the neonatal immune system in the regulation of CD4 expression by costimulation.

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Activation Associated ERK1/2 Signaling Impairments in CD8+ T Cells Co-Localize with Blunted Polyclonal and HIV-1 Specific Effector Functions in Early Untreated HIV-1 Infection

PLoS ONE ◽

10.1371/journal.pone.0077412 ◽

2013 ◽

Vol 8 (10) ◽

pp. e77412 ◽

Cited By ~ 4

Author(s):

Timothy Q. Crawford ◽

Fredrick M. Hecht ◽

Christopher D. Pilcher ◽

Lishomwa C. Ndhlovu ◽

Jason D. Barbour

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Effector Functions ◽

Specific Effector ◽

Hiv 1

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Epithelial adhesion molecules can inhibit HIV-1–specific CD8+ T-cell functions

Blood ◽

10.1182/blood-2010-12-321588 ◽

2011 ◽

Vol 117 (19) ◽

pp. 5112-5122 ◽

Cited By ~ 15

Author(s):

Hendrik Streeck ◽

Douglas S. Kwon ◽

Augustine Pyo ◽

Michael Flanders ◽

Mathieu F. Chevalier ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Antigenic Stimulation ◽

Effector Functions ◽

Cell Functions ◽

Natural Ligand ◽

Inhibitory Molecules ◽

Hiv 1 ◽

E Cadherin

Abstract Under persistent antigenic stimulation, virus-specific CD8+ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.7, P = .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1hi HIV-1–specific CD8+ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P = .002) and to inhibit viral replication (P = .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1hi-expressing HIV-1–specific CD8+ T cells systemically.

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Alterations in T-Cell Receptor Vβ Repertoire of CD4 and CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Children

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.1.53-58.2003 ◽

2003 ◽

Vol 10 (1) ◽

pp. 53-58 ◽

Cited By ~ 15

Author(s):

Monica Kharbanda ◽

Thomas W. McCloskey ◽

Rajendra Pahwa ◽

Mei Sun ◽

Savita Pahwa

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Chronic Phase ◽

Cell Receptor ◽

Cd8 T Lymphocytes ◽

Immunodeficiency Virus

ABSTRACT Perturbations in the T-cell receptor (TCR) Vβ repertoire were assessed in the CD4 and CD8 T lymphocytes of human immunodeficiency virus (HIV)-infected children who were receiving therapy during the chronic phase of infection by flow cytometry (FC) and PCR analysis. By FC, representation of 21 TCR Vβ subfamilies was assessed for an increased or decreased percentage in CD4 and CD8 T cells, and by PCR, 22 TCR Vβ subfamilies of CD4 and CD8 T cells were analyzed by CDR3 spectratyping for perturbations and reduction in the number of peaks, loss of Gaussian distribution, or clonal dominance. The majority of the TCR Vβ subfamilies were examined by both methods and assessed for deviation from the norm by comparison with cord blood samples. The CD8-T-lymphocyte population exhibited more perturbations than the CD4 subset, and clonal dominance was present exclusively in CD8 T cells. Of the 55 total CD8-TCR Vβ families classified with clonal dominance by CDR3 spectratyping, only 18 of these exhibited increased expression by FC. Patients with high numbers of CD8-TCR Vβ families with decreased percentages had reduced percentages of total CD4 T cells. Increases in the number of CD4-TCR Vβ families with increased percentages showed a positive correlation with skewing. Overall, changes from normal were often discordant between the two methods. This study suggests that the assessment of HIV-induced alterations in TCR Vβ families at cellular and molecular levels yields different information and that our understanding of the immune response to HIV is still evolving.

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

Blood ◽

10.1182/blood.v98.6.1667 ◽

2001 ◽

Vol 98 (6) ◽

pp. 1667-1677 ◽

Cited By ~ 169

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.

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HIV-1–specific cytotoxicity is preferentially mediated by a subset of CD8+ T cells producing both interferon-γ and tumor necrosis factor–α

Blood ◽

10.1182/blood-2003-12-4341 ◽

2004 ◽

Vol 104 (2) ◽

pp. 487-494 ◽

Cited By ~ 88

Author(s):

Mathias Lichterfeld ◽

Xu G. Yu ◽

Michael T. Waring ◽

Stanley K. Mui ◽

Mary N. Johnston ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Tumor Necrosis ◽

Interferon Γ ◽

Effector Functions ◽

Tnf Α ◽

Specific Cytotoxicity ◽

Factor Α ◽

Hiv 1 ◽

Necrosis Factor

Abstract CD8+ T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8+ T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8+ T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8+ T cells secreting interferon-γ but no tumor necrosis factor-α (TNF-α) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P = .57), a subset of CD8+ T cells secreting both inter-feron-γ and TNF-α was substantially more strongly associated with cytotoxicity (R = 0.67, P < .001). This subset of CD8+ T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex vivo HIV-1-specific cytoxicity than CD8+ T cells secreting solely interferon-γ following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8+ T cells is preferentially mediated by a subset of CD8+ T cells secreting both interferon-γ and TNF-α. (Blood. 2004;104:487-494)

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Epigenetic Control of Interferon-Gamma Expression in CD8 T Cells

Journal of Immunology Research ◽

10.1155/2015/849573 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 22

Author(s):

Patrícia S. de Araújo-Souza ◽

Steffi C. H. Hanschke ◽

João P. B. Viola

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Cd8 T Cells ◽

Molecular Mechanisms ◽

Epigenetic Modification ◽

Cd8 T Lymphocytes ◽

Conserved Noncoding Sequences ◽

Differential Gene ◽

Posttranslational Histone Modifications ◽

Th 1

Interferon- (IFN-)γis an essential cytokine for immunity against intracellular pathogens and cancer. IFN-γexpression by CD4 T lymphocytes is observed only after T helper (Th) 1 differentiation and there are several studies about the molecular mechanisms that control Ifng expression in these cells. However, naïve CD8 T lymphocytes do not produce large amounts of IFN-γ, but after TCR stimulation there is a progressive acquisition of IFN-γexpression during differentiation into cytotoxic T lymphocytes (CTL) and memory cells, which are capable of producing high levels of this cytokine. Differential gene expression can be regulated from the selective action of transcriptional factors and also from epigenetic mechanisms, such as DNA CpG methylation or posttranslational histone modifications. Recently it has been recognized that epigenetic modification is an integral part of CD8 lymphocyte differentiation. This review will focus on the chromatin status of Ifng promoter in CD8 T cells and possible influences of epigenetic modifications in Ifng gene and conserved noncoding sequences (CNSs) in regulation of IFN-γproduction by CD8 T lymphocytes.

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Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study

European Heart Journal ◽

10.1093/eurheartj/ehaa703 ◽

2020 ◽

Vol 41 (37) ◽

pp. 3549-3560 ◽

Cited By ~ 2

Author(s):

David M Leistner ◽

Nicolle Kränkel ◽

Denitsa Meteva ◽

Youssef S Abdelwahed ◽

Claudio Seppelt ◽

...

Keyword(s):

T Cells ◽

Acute Coronary Syndrome ◽

T Cell ◽

T Lymphocytes ◽

Cd8 T Cells ◽

Coronary Plaque ◽

Effector Molecules ◽

Coronary Syndrome ◽

Fibrous Cap ◽

Cd8 T Lymphocytes

Abstract Aims Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. Methods and results The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. Conclusions The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. Trial registration The study was registered at clinicalTrials.gov (NCT03129503).

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