Rapid Perturbation in Viremia Levels Drives Increases in Functional Avidity of HIV-specific CD8 T Cells

Viganó, Selena; Enders, Felicitas Bellutti; Miconnet, Isabelle; Cellerai, Cristina; Savoye, Anne-Laure; Rozot, Virginie; Perreau, Matthieu; Faouzi, Mohamed; Ohmiti, Khalid; Cavassini, Matthias; Bart, Pierre‐Alexandre; Pantaleo, Giuseppe; Harari, Alexandre

doi:10.1371/journal.ppat.1003423

Cited by 23 publications

(41 citation statements)

References 72 publications

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“…Moreover, several studies in active chronic infections established links between the magnitude of T-cell stimulation (or TCR avidity) and T-cell fate. Accordingly, lower avidity or weaker stimulated T-cells are more prone to retain a normal phenotype while higher avidity T-cells acquire a chronic infection phenotype or become deleted 62,63 . This is somewhat reminiscent of the fact that T-cells retain a rather normal effector phenotype in latent infections in which T-cells most likely receive lower TCR stimulation due to a lower level of antigen-exposure.…”

Section: Infections Which Show a Latent Phase (For Example Epstein-bamentioning

confidence: 99%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

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Section: Infections Which Show a Latent Phase (For Example Epstein-bamentioning

confidence: 99%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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“…In contrast to CD8 C T cells, CD4 C T cells recognize epitopes presented by MHC class II molecules and libraries of longer (20-mer) overlapping peptides are generally used to screen for antigen-specific responses. 19 We thus measured the response of Melan-A/ MART-1 [25][26][27][28][29][30][31][32][33][34][35][36] -specific CD4 C T-cell clones 20 spiked into PBMCs of HLA-DQ6 C donors in the presence of 20-mers overlapping peptide pools (1 mM each). As shown in Fig.…”

Section: Apc-mediated Stimulationmentioning

confidence: 99%

“…CD4 C blasts were used after at least 10 d of culture. For long-term in vitro stimulation, PBMCs from 5 HLA-A2C donors were stimulated in 24 well-plates (4 £ 10 6 cells/ well) for one week with 0.1 mM Melan-A [26][27][28][29][30][31][32][33][34][35] (A27L) in the presence or absence of MAGE-A3 peptide pool (0.1 mM each peptide). After 48 h of incubation at 37 C, 100 U/mL IL-2 were added to the culture.…”

Section: In Vitro Stimulationmentioning

confidence: 99%

“…EC50 was determined as the peptide concentration needed to achieve a half-maximal response as previously described. 27 Intracellular cytokine staining / Flow cytometry IFNg and TNF-a cytokine secretion was investigated by ICS. The following monoclonal antibodies were used at predetermined optimal concentrations: anti-CD3¡PerCP-Cy5.5 (eBioscience), anti-CD8 C ¡AF488, anti-CD4¡PE-Cy7, antiIFNg¡BV421, anti-TNFa¡AF647 (Biolegend).…”

Section: In Vitro Stimulationmentioning

confidence: 99%

“…The background obtained with corresponding irrelevant peptide pools alone or non-stimulated cells were subtracted from values obtained in the presence of cognate peptide C irrelevant peptide pool or specific peptide alone, respectively. The proliferation of Melan-A 26-35 -specific CD8 C T cells was assessed by tetramer staining using PE-labeled Melan-A [26][27][28][29][30][31][32][33][34][35] tetramer (TcMetrix), FITC conjugated CD8 C and aqua live/ dead stain kit.…”

Section: In Vitro Stimulationmentioning

confidence: 99%

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High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

et al. 2015

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In immune intervention trials, the comprehensive investigation of immunogenicity or T-cell epitope-mapping is challenging especially when a large set of epitopes needs to be screened and limited sample material is available. To this end, T-cell responses are often monitored using peptide pools. Here, we assessed the magnitude and sensitivity of detection of antigen-specific CD8 C and CD4 C T cells using a single peptide alone or mixed into large pools. Interestingly the magnitude of ex vivo anti-viral and anti-tumor T-cell responses was identical irrespective of the presence and number of irrelevant peptides, in different functional assays with PBMCs from healthy donors and cancer patients. Moreover, the presence of up to 300 irrelevant peptides did not affect the threshold of responsiveness of antigen-specific CD8 C T cells to single cognate peptides. These data demonstrate the relevance of using very large peptide pools for the sensitive and specific immune-monitoring of epitope-specific T cells in natural or immunemodulated context.

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Standardization and quality control for high‐dimensional mass cytometry studies of human samples

et al. 2016

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Mass cytometry (CyTOF), a mass spectrometry-based single cell phenotyping technology, allows utilization of over 35 antibodies in a single sample and is a promising tool for translational human immunology studies. Although several analysis tools are available to interpret the complex data sets generated, a robust method for standardization and quality control within and across studies is needed. Here we report an efficient and easily adaptable method to monitor quality of individual samples in human immunology studies and to facilitate reproducible data analysis. Samples to be assessed are spiked with a defined amount of reference peripheral blood mononuclear cells from a healthy donor, derived from a single large blood draw. The presence of known standardized numbers and phenotypic profiles of these reference cells greatly facilitates sample analysis by allowing for: 1) quality control for consistent staining of each antibody in the panel, 2) identification of potential batch effects, and 3) implementation of a robust gating strategy. We demonstrate the utility of this method using peripheral blood and bronchoalveolar lavage samples from HIV+ patients by characterizing their CD8+ T-cell phenotypes and cytokine expression, respectively. Our results indicate that this method allows quality control of experimental conditions and results in highly reproducible population frequencies through a robust gating strategy.

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Rapid Perturbation in Viremia Levels Drives Increases in Functional Avidity of HIV-specific CD8 T Cells

Cited by 23 publications

References 72 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

Standardization and quality control for high‐dimensional mass cytometry studies of human samples

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