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

Scott‐Algara, Daniel; Buseyne, Florence; Porrot, Françoise; Corre, Béatrice; Bellal, Nassima; Rouzioux, Christine; Blanche, Stéphane; Rivière, Yves

doi:10.1007/s10875-005-0358-3

Cited by 14 publications

(13 citation statements)

References 53 publications

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“…Against HPV infected tumor cells, the CD56+ subset was much more cytotoxic than CD56- cells despite high levels of HPV specific CD56- CD8 T cells [10]. We know that only a fraction of HIV tetramer positive cells produce perforin [35], [39] and this reinforces a view that epitope specificity is not a marker for cytolytic effector function in CD8 T cells. We believe that the tetramer binding CD56+ CD8 T cell subset defines the most potent, virus-specific lytic effectors.…”

Section: Discussionmentioning

confidence: 89%

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Poonia

Pauza

2014

PLoS ONE

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Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART.Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease.

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Section: Discussionmentioning

confidence: 89%

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Poonia

Pauza

2014

PLoS ONE

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“…64 There is little information regarding the role of TGF-b in controlling CD8 þ immune responses during lentiviral infections, but there is ample evidence for CD8 þ immune dysfunction during the course of AIDS lentiviral infections. 1,2,5,65,66 In considering possible mechanisms for CD8 þ dysfunction, we hypothesized that FIV infection may cause increased TGF-bRII expression on CD8 þ lymphocytes, thereby making them much more sensitive to TGF-b inhibition. Figures 5 and 6 demonstrate that CD8 þ lymphocytes from FIV þ cats have increased surface expression of TGF-bRII when compared to FIV -cats and these findings suggest that there is progressive upregulation of TGF-bRII during the course of FIV infection.…”

Section: Cd25mentioning

confidence: 99%

CD4⁺CD25⁺T Regulatory Cells Inhibit CD8⁺IFN-γ Production During Acute and Chronic FIV Infection Utilizing a Membrane TGF-β-Dependent Mechanism

Fogle

Mexas

Tompkins

et al. 2010

AIDS Research and Human Retroviruses

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CD8þ lymphocytes are critical to the control and elimination of viral pathogens. Impaired CD8 þ responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8 þ impairment remain elusive. Using the feline immunodeficiency virus (FIV) model for human AIDS, we reported previously that CD4 þ CD25 þ Treg cells in both the acute and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4 þ CD25-T cell responses. In the current study, we have demonstrated that CD4 þ CD25 þ Treg cells suppress CD8 þ responses to immune stimulation during both the acute and chronic, asymptomatic phase of FIV infection and that the mechanism of suppression may be mediated by membrane-þ lymphocytes from lymph node suspensions significantly enhanced production of IFN-g during the acute phase of infection and coculture of CD8 þ lymphocytes with CD4 þ CD25 þ lymphocytes resulted in suppression of CD8 þ IFN-g during both the acute and chronic stages of infection. FACS analysis indicated that there was TGF-bRII upregulation on CD8 CD25þ subset in chronically infected cats. In support of activation of the TGF-b signaling pathway, Western blotting showed Smad 2 phosphorylation in CD8coculture. These results demonstrate the suppressive effect CD4 þ CD25 þ Treg cells have on the CD8 þ immune response during the acute and chronic stages of FIV infection and suggest that the mechanism of suppression may be mediated by mTGF-b.

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“…Few studies have described CTL in early perinatal HIV-1 (3,17). However, it is unclear whether rapid progression in infants occurs in association with an undetectable HIV-specific CTL response or with an ineffective HIV-specific CTL response (21). This distinction is of relevance to pediatric HIV vaccine design strategies.…”

mentioning

confidence: 99%

Unique Acquisition of Cytotoxic T-Lymphocyte Escape Mutants in Infant Human Immunodeficiency Virus Type 1 Infection

Pillay

Zhang

Drijfhout

et al. 2005

J Virol

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The role of cytotoxic T-lymphocyte (CTL) escape in rapidly progressive infant human immunodeficiency virus type 1 (HIV-1) infection is undefined. The data presented here demonstrate that infant HIV-1-specific CTL can select for viral escape variants very early in life. These variants, furthermore, may be selected specifically in the infant, despite the same CTL specificity being present in the mother. Additionally, pediatric CTL activity may be compromised both by the transmission of maternal escape variants and by mother-to-child transmission of escape variants that originally arose in the father. The unique acquisition of these CTL escape forms may help to explain the severe nature of some pediatric HIV infections.

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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

Cited by 14 publications

References 53 publications

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

CD4⁺CD25⁺T Regulatory Cells Inhibit CD8⁺IFN-γ Production During Acute and Chronic FIV Infection Utilizing a Membrane TGF-β-Dependent Mechanism

Unique Acquisition of Cytotoxic T-Lymphocyte Escape Mutants in Infant Human Immunodeficiency Virus Type 1 Infection

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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

Cited by 14 publications

References 53 publications

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

CD4+CD25+T Regulatory Cells Inhibit CD8+IFN-γ Production During Acute and Chronic FIV Infection Utilizing a Membrane TGF-β-Dependent Mechanism

Unique Acquisition of Cytotoxic T-Lymphocyte Escape Mutants in Infant Human Immunodeficiency Virus Type 1 Infection

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CD4⁺CD25⁺T Regulatory Cells Inhibit CD8⁺IFN-γ Production During Acute and Chronic FIV Infection Utilizing a Membrane TGF-β-Dependent Mechanism