Potent HIV-specific responses are enriched in a unique subset of CD8+ T cells that coexpresses CD4 on its surface

Zloza, Andrew; Schenkel, Jason M.; Tenorio, Allan R.; Martinson, Jeffrey; Jeziorczak, Paul M.; Al‐Harthi, Lena

doi:10.1182/blood-2009-02-202481

Cited by 38 publications

(46 citation statements)

References 33 publications

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“…This new technique should also facilitate the enumeration of unique subsets of cells induced in natural infections that have noncanonical states of differentiation or lineages but potent functional responses (39). One specific advantage gained by using microfabricated systems for these analyses is that the number of cells required is small and is, therefore, conducive to evaluating mucosal samples or other clinical samples with limited numbers of cells (e.g., pediatric samples).…”

Section: Discussionmentioning

confidence: 99%

A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis

Varadarajan¹,

Jülg²,

Yamanaka³

et al. 2011

J. Clin. Invest.

144

136

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CD8 + T cells are a key component of the adaptive immune response to viral infection. An inadequate CD8 +T cell response is thought to be partly responsible for the persistent chronic infection that arises following infection with HIV. It is therefore critical to identify ways to define what constitutes an adequate or inadequate response. IFN-γ production has been used as a measure of T cell function, but the relationship between cytokine production and the ability of a cell to lyse virus-infected cells is not clear. Moreover, the ability to assess multiple CD8 + T cell functions with single-cell resolution using freshly isolated blood samples, and subsequently to recover these cells for further functional analyses, has not been achieved. As described here, to address this need, we have developed a high-throughput, automated assay in 125-pl microwells to simultaneously evaluate the ability of thousands of individual CD8 + T cells from HIV-infected patients to mediate lysis and to produce cytokines. This concurrent, direct analysis enabled us to investigate the correlation between immediate cytotoxic activity and short-term cytokine secretion. The majority of in vivo primed, circulating HIV-specific CD8 + T cells were discordant for cytolysis and cytokine secretion, notably IFN-γ, when encountering cognate antigen presented on defined numbers of cells. Our approach should facilitate determination of signatures of functional variance among individual effector CD8 + T cells, including those from mucosal samples and those induced by vaccines.

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Section: Discussionmentioning

confidence: 99%

A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis

Varadarajan¹,

Jülg²,

Yamanaka³

et al. 2011

J. Clin. Invest.

144

136

View full text Add to dashboard Cite

show abstract

“…While the role of CD4 ϩ CD8 ϩ double-positive cells is not entirely clear, they are known to exhibit cytolytic activity as well as the antigen-dependent secretion of gamma interferon (IFN-␥) and IL-2. Moreover, they are enriched for HIV-specific responses in chronically infected patients (39,64,82,95). Importantly, these cells are reported to express the CD8␣/␤ heterodimer (64,81 14%, respectively) (Fig.…”

Section: Vol 85 2011mentioning

confidence: 99%

HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements

Leonard

Filzen²,

Carter

et al. 2011

J Virol

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The Nef protein is an important HIV virulence factor that promotes the degradation of host proteins to augment virus production and facilitate immune evasion. The best-characterized targets of Nef are major histocompatibility complex class I (MHC-I) and CD4, but Nef also has been reported to target several other proteins, including CD8␤, CD28, CD80, CD86, and CD1d. To compare and contrast the effects of Nef on each protein, we constructed a panel of chimeric proteins in which the extracellular and transmembrane regions of the MHC-I allele HLA-A2 were fused to the cytoplasmic tails of CD4, CD28, CD8␤, CD80, CD86, and CD1d. We found that Nef coprecipitated with and disrupted the expression of molecules with cytoplasmic tails from MHC-I HLA-A2, CD4, CD8␤, and CD28, but Nef did not bind to or alter the expression of molecules with cytoplasmic tails from CD80, CD86, and CD1d. In addition, we used short interfering RNA (siRNA) knockdown and coprecipitation experiments to implicate AP-1 as a cellular cofactor for Nef in the downmodulation of both CD28 and CD8␤. The interaction with AP-1 required for CD28 and CD8␤ differed from the AP-1 interaction required for MHC-I downmodulation in that it was mediated through the dileucine motif within Nef (LL 164,165 AA) and did not require the tyrosine binding pocket of the AP-1 subunit. In addition, we demonstrate a requirement for ␤-COP as a cellular cofactor for Nef that was necessary for the degradation of targeted molecules HLA-A2, CD4, and CD8. These studies provide important new information on the similarities and differences with which Nef affects intracellular trafficking and help focus future research on the best potential pharmaceutical targets.

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“…Tc2 cells produce IL-4, IL-5, IL-10, and IL-13 but not IFN-␥. CD4 dim CD8 bright T cells produce predominantly IL-4 in response to staphylococcal enterotoxin B or antiCD3/CD28, whereas antigen-specific CD4 dim CD8 bright T cells produce polyfunctional Tc1 and Tc2 cytokines in response to recall antigens [19], suggesting that the cytokine secretion profiles, dependent upon the mode of stimulation, serve to control the differentiation of naive CD8 ϩ T cells (reviewed in [20]). IFN-␥ production by CD8 ϩ T cells in antiretroviral-treated, HIV-1-infected individuals was demonstrated to be maximal only upon CD4 ϩ T cell recovery, whereas IL-2 production was seen early in these patients, even when CD4 ϩ T cell recovery was minimal [21].…”

Section: Introductionmentioning

confidence: 99%

Human immunodeficiency virus-1 infection protects against a Tc1-to-Tc2 shift in CD8+ T cells

et al. 2011

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Potent HIV-specific responses are enriched in a unique subset of CD8+ T cells that coexpresses CD4 on its surface

Cited by 38 publications

References 33 publications

A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis

A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis

HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements

Human immunodeficiency virus-1 infection protects against a Tc1-to-Tc2 shift in CD8+ T cells

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