ORCID Profile
0000-0001-6617-5995
Current Organisation
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2022
DOI: 10.1101/2022.07.22.22277947
Abstract: Long-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent in iduals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)- specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, rather than the effector T- bet+, cytotoxic granzymes+ and perforin+ cells seen in high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing erse TCR repertoires, that were absent in in iduals with low antibody levels. However, vaccination in low antibody convalescent in iduals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD- region should be prioritized in booster vaccines. In iduals with low neutralising antibody titres may be at risk of SARS-CoV-2 re-infection due to a failure to generate a high quality CD4 T cell response specific for receptor binding domain (RBD), including memory CD4 T cells that proliferate in vitro in response to RBD, and which are also therefore an important target for vaccine design.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2021
DOI: 10.1101/2021.06.01.21257759
Abstract: A proportion of patients surviving acute COVID-19 infection develop post-COVID syndrome (long COVID) encompassing physical and neuropsychiatric symptoms lasting longer than 12 weeks. Here we studied a prospective cohort of in iduals with long COVID compared to age/gender matched subjects without long COVID (from the ADAPT study), healthy donors and in iduals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found highly activated innate immune cells and an absence of subsets of un-activated naïve T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. These activated myeloid cells may contribute to the elevated levels of type I (IFN-β) and III interferon (IFN-λ1) that remained persistently high in long COVID subjects at 8 months post-infection. We found positive inter-analyte correlations that consisted of 18 inflammatory cytokines in symptomatic long COVID subjects that was not observed in asymptomatic COVID-19 survivors. A linear classification model was used to exhaustively search through all 20475 combinations of the 29 analytes measured, that had the strongest association with long COVID and found that the best 4 analytes were: IL-6, IFN-γ, MCP-1 (CCL2) and VCAM-1. These four inflammatory biomarkers gave an accuracy of 75.9%, and an F1 score of 0.759, and have also previously been associated with acute severe disease. In contrast, plasma ACE2 levels, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.
Publisher: The Company of Biologists
Date: 2016
DOI: 10.1242/JCS.181248
Abstract: Memory T cells are characterised by their rapid transcriptional programs upon re-stimulation. This transcriptional memory (TM) response is facilitated by permissive chromatin but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4+ T cells, we show that the signaling enzyme, protein kinase C-theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to TM-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4+ T cells. Within the nucleus, PKC-θ catalytic activity maintains p65 Ser536 phosphorylation and can directly influence chromatin accessibility at TM genes by regulating H2B deposition via Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2022
DOI: 10.1101/2022.06.07.22276020
Abstract: Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12- months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p .001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p .001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.
Publisher: Wiley
Date: 29-04-2014
Abstract: Human Ag-specific CD4(+) T cells can be detected by their dual expression of CD134 (OX40) and CD25 after a 44 hours stimulation with cognate Ag. We show that surface expression of CD39 on Ag-specific cells consistently identifies a substantial population of CD4(+) CD25(+) CD134(+) CD39(+) T cells that have a Treg-cell-like phenotype and mostly originate from bulk memory CD4(+) CD45RO(+) CD127(low) CD25(high) CD39(+) Treg cells. Viable, Ag-specific CD25(+) CD134(+) CD39(+) T cells could be expanded in vitro as cell lines and clones, and retained high Forkhead Box Protein 3, CTLA-4 and CD39 expression, suppressive activity and Ag specificity. We also utilised this combination of cell surface markers to measure HIV-Gag responses in HIV(+) patients before and after anti-retroviral therapy (ART). Interestingly, we found that the percentage of CD39(-) cells within baseline CD4(+) T-cell responses to HIV-Gag was negatively correlated with HIV viral load pre-ART and positively correlated with CD4(+) T-cell recovery over 96 weeks of ART. Collectively, our data show that Ag-specific CD4(+) CD25(+) CD134(+) CD39(+) T cells are highly enriched for Treg cells, form a large component of recall responses and maintain a Treg-cell-like phenotype upon in vitro expansion. Identification and isolation of these cells enables the role of Treg cells in memory responses to be further defined and provides a development pathway for novel therapeutics.
Publisher: Elsevier BV
Date: 04-2022
Publisher: Wiley
Date: 09-05-2017
DOI: 10.1038/ICB.2017.28
Publisher: eLife Sciences Publications, Ltd
Date: 24-12-2021
DOI: 10.7554/ELIFE.50324
Abstract: Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected in iduals, which decreased following ART. Stimulation of THP1 monocytes with R5 tropic HIV BAL potently activated MAIT cells in vitro. This activation was dependent on IL-12 and IL-18 but was independent of the TCR. Upon activation, MAIT cells were able to upregulate granzyme B, IFNγ and HIV-1 restriction factors CCL3, 4, and 5. Restriction factors produced by MAIT cells inhibited HIV-1 infection of primary PBMCs and immortalized target cells in vitro. These data reveal MAIT cells to be an additional T cell population responding to HIV-1, with a potentially important role in controlling viral replication at mucosal sites.
Publisher: Cold Spring Harbor Laboratory
Date: 02-2022
DOI: 10.1101/2022.01.30.478400
Abstract: Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored erse polyclonal SARS-CoV- 2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. More naïve interferon-activated CD4 + T cells were recruited into the memory compartment and recovery was associated with the development of robust CD4 + memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection. Children have erse polyclonal SARS-CoV-2-specific naïve T cells Adults have clonally expanded exhausted SARS-CoV-2-specific memory T cells Interferon-activated naïve T cells differentiate into memory T cells in adults but not children Adults but not children develop robust memory T cell responses to SARS-CoV-2
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.MOLCEL.2011.02.030
Abstract: Studies in yeast demonstrate that signaling kinases have a surprisingly active role in the nucleus, where they tether to chromatin and modulate gene expression programs. Despite these seminal studies, the nuclear mechanism of how signaling kinases control transcription of mammalian genes is in its infancy. Here, we provide evidence for a hitherto unknown function of protein kinase C-theta (PKC-θ), which physically associates with the regulatory regions of inducible immune response genes in human T cells. Chromatin-anchored PKC-θ forms an active nuclear complex by interacting with RNA polymerase II, the histone kinase MSK-1, and the adaptor molecule 14-3-3ζ. ChIP-on-chip reveals that PKC-θ binds to promoters and transcribed regions of genes, as well as to microRNA promoters that are crucial for cytokine regulation. Our results provide a molecular explanation for the role of PKC-θ not only in normal T cell function, but also in circumstances of its ectopic expression in cancer.
Publisher: Public Library of Science (PLoS)
Date: 04-10-2013
Publisher: Wiley
Date: 18-12-2012
Abstract: The fine control of T-cell differentiation and its impact on HIV disease states is poorly understood. In this study, we demonstrate that B-lymphocyte-induced maturation protein-1 (Blimp-1/Prdm1) is highly expressed in CD4(+) T cells from chronically HIV-infected (CHI) patients compared to cells from long-term nonprogressors or healthy controls. Stimulation through the T-cell receptor in the presence of IL-2 induces Blimp-1 protein expression. We show here that Blimp-1 levels are translationally regulated by microRNA-9 (miR-9). Overexpression of miR-9 induces Blimp-1 repression, restoring IL-2 secretion in CD4(+) T cells via reduction in the binding of Blimp-1 to the il-2 promoter. In CHI patients where IL-2 expression is reduced and there is generalized T-cell dysfunction, we show differential expression of both miR-9 and Blimp-1 in CD4(+) cells compared with levels in long-term nonprogressors. These data identify a novel miR-9/Blimp-1/IL-2 axis that is dysregulated in progressive HIV infection.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1038/S41385-019-0180-2
Abstract: Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell-T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + in iduals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one in idual. As previously shown for blood, CD32
Publisher: MDPI AG
Date: 12-08-2015
Publisher: Springer Science and Business Media LLC
Date: 13-01-2022
DOI: 10.1038/S41590-021-01113-X
Abstract: A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied in iduals with LC compared to age- and gender-matched recovered in iduals without LC, unexposed donors and in iduals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
Publisher: Elsevier
Date: 2020
Publisher: Frontiers Media SA
Date: 30-07-2015
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.27.23294704
Abstract: This study investigated the humoral and cellular immune responses in in iduals with long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24-months. LC participants showed elevated spike and nucleocapsid IgG levels, higher neutralizing capacity, and increased spike- and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells at 3- and 8-months, but these differences did not persist at 24-months. Some LC participants had detectable IFN-γ and IFN-β, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at 24-month timepoint revealed similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC. No significant differences in exhaustion scores or antigen-specific T cell clones were observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24-months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count were associated with improvements in health-related quality of life.
Publisher: Frontiers Media SA
Date: 21-04-2017
Publisher: Frontiers Media SA
Date: 08-08-2019
Publisher: Wiley
Date: 09-06-2022
DOI: 10.1002/AJH.26619
Abstract: Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID‐19. Patients and healthy controls (HC N = 13) received two doses of BNT162b2: follicular lymphoma (FL N = 35) who were treatment naïve (TN N = 11) or received immunochemotherapy (ICT N = 23) and Waldenström's macroglobulinemia (WM N = 37) including TN ( N = 9), ICT ( N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi N = 12). Anti‐spike immunoglobulin G (IgG) was determined by a high‐sensitivity flow‐cytometric assay, in addition to live‐virus neutralization. Antigen‐specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup ( N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti‐spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25‐fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti‐spike IgG correlated with lymphocyte count ( r = .63 p = .002), and time from treatment ( r = .56 p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis ( p = .03). In the WM cohort, median anti‐spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC ( p .0001). Anti‐spike IgG correlated with neutralization of the delta variant ( r = .62, p .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p .0001) for early‐clade and delta. All cohorts had functional T cell responses. Median anti‐spike IgG decreased 4‐fold from second to third dose ( p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant.
Publisher: MDPI AG
Date: 18-01-2021
DOI: 10.3390/IJMS22020912
Abstract: HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4% p = 0.002) and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3% p 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.
Publisher: Frontiers Media SA
Date: 04-05-2018
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Chansavath Phetsouphanh.