Rapid turnover of T cells in acute infectious mononucleosis

Macallan, Derek C.; Wallace, Diana L.; Irvine, Andrew J; Asquith, Becca; Worth, Andrew; Ghattas, Hala; Zhang, Yan; Griffin, George E.; Tough, David F.; Beverley, Peter C. L.

doi:10.1002/eji.200324295

Cited by 40 publications

(42 citation statements)

References 33 publications

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“…23 The lack of increased NK cell labelling in acute EBV infection is surprising and contrasts with the dramatic proliferative responses seen in mice with MCMV infection 1 and with the massive CD4 and CD8 lymphocyte proliferative response occurring at the same time in the same individuals in whom proliferation rates for CD8 + CD45R0 + T cells were 100 times normal. 26 Despite this lack of labelling, there did appear to be expansion of the circulating NK cell pool, consistent with, although less marked than, the findings of a previous study in AIM in which NK cell numbers at diagnosis were increased 6-fold 24 and the total production rate of NK cells did appear to be related to clinical severity.…”

Section: Discussionsupporting

confidence: 70%

“…This approach has been successfully applied to investigate T-and B-lymphocyte kinetics in human studies in health and disease. [25][26][27][28][29] Firstly, we set out to investigate the kinetics of normal NK cells in terms of the lag between mitosis and appearance in the circulation, the production rate of new cells, and their disappearance rate from the circulation. Secondly, we investigated the effects of ageing on NK cell dynamics.…”

Section: Discussionmentioning

confidence: 99%

“…Although this lack of increased enrichment in NK cells in AIM is surprising, when increased cell numbers were taken into account, mean production rates tended to be higher than in healthy young controls, although not reaching statistical significance in this small group (P ¼ 0Á08). There was good correlation of the total NK production rate with the clinical severity score 26 and with the total blood lymphocyte count (r ¼ 0Á81 and r ¼ 0Á76, respectively), although with only five subjects these relationships were not statistically significant.…”

Section: The Effect Of Acute Viral Infection On Nk Cell Dynamicsmentioning

confidence: 92%

“…In order to study NK cell kinetics in health, to assess the impact of ageing and to investigate the impact of acute and chronic infection, subjects were recruited from four groups: firstly, young healthy subjects [n ¼ 5; three male and two female subjects; median age (range) 22 (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)) years]; secondly, healthy elderly subjects [n ¼ 8; two male and six female subjects; median age (range) 78 (65-85) years] as previously described; 29 thirdly, subjects with chronic HTLV-I infection [n ¼ 5; one male and four female subjects; median age (range) 48 (39-72) years]; and fourthly, five subjects with acute infectious mononucleosis (AIM) as a result of acute EBV infection [n ¼ 5; four male and one female subject; median age (range) 19 (18-21) years, as previously described 30 ]. All subjects with AIM had been previously healthy; all had a positive monospot test and EBV-specific immunoglobulin M (IgM) in the context of fever, pharyngitis and fatigue.…”

Section: Subjectsmentioning

confidence: 99%

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In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection

et al. 2007

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Summary Human natural killer (NK) cells form a circulating population in a state of dynamic homeostasis. We investigated NK cell homeostasis by labelling dividing cells in vivo using deuterium‐enriched glucose in young and elderly healthy subjects and patients with viral infection. Following a 24‐hr intravenous infusion of 6,6‐D2‐glucose, CD3– CD16+ NK cells sorted from peripheral blood mononuclear cells (PBMC) by fluorescence‐activated cell sorter (FACS) were analysed for DNA deuterium content by gas chromatography mass spectrometry to yield minimum estimates for proliferation rate (p). In healthy young adults (n = 5), deuterium enrichment was maximal ∼ 10 days after labelling, consistent with postmitotic maturation preceding circulation. The mean (± standard deviation) proliferation rate was 4·3 ± 2·4%/day (equivalent to a doubling time of 16 days) and the total production rate was 15 ± 7·6 × 106 cells/l/day. Labelled cells disappeared from the circulation at a similar rate [6·9 ± 4·0%/day; half‐life (T½) < 10 days]. Healthy elderly subjects (n = 8) had lower proliferation and production rates (P = 2·5 ± 1·0%/day and 7·3 ± 3·7 × 106 cells/l/day, respectively; P = 0·04). Similar rates were seen in patients chronically infected with human T‐cell lymphotropic virus type I (HTLV‐I) (P = 3·2 ± 1·9%/day). In acute infectious mononucleosis (n = 5), NK cell numbers were increased but kinetics were unaffected (P = 2·8 ± 1·0%/day) a mean of 12 days after symptom onset. Human NK cells have a turnover time in blood of about 2 weeks. Proliferation rates appear to fall with ageing, remain unperturbed by chronic HTLV‐I infection and normalize rapidly following acute Epstein–Barr virus infection.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: The Effect Of Acute Viral Infection On Nk Cell Dynamicsmentioning

confidence: 92%

Section: Subjectsmentioning

confidence: 99%

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In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection

et al. 2007

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“…In addition, deuterated glucose, which is incorporated into cells upon proliferation, enables monitoring the dynamics of clonal expansions in patients upon treatment. 92 pMHC multimers have proven to be valuable tools for the identification and enumeration of CD8 ϩ T cells present in PBMC, whose TCR recognises a given TA-derived antigenic peptide. Nevertheless, the TCR can exhibit promiscuity in pMHC binding, and specificity of the binding-interaction has been claimed to be temperature dependent.…”

Section: Immune Monitoringmentioning

confidence: 99%

Recent advances in tumour antigen‐specific therapy: In vivo veritas

Mahnke

Speiser

Luescher

et al. 2004

Intl Journal of Cancer

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Modern cancer therapies should strive not only to eliminate malignant tissues but also to preserve healthy tissues and the patient's quality of life. Antigen-specific immunotherapy approaches are promising for either aspect since they are designed to only act against tissues expressing 1 or more specified tumour antigens. In order to develop successful vaccine and adoptive transfer protocols, longitudinal monitoring of cancer patients taking part in clinical trials is mandatory. Here, in vivo expansion of antigenspecific cells, as well as their ex vivo functional status represent important parameters to be analysed. To obtain results that most closely reflect the cells' in vivo status, functional assays must be carried out with as little in vitro culturing as possible. The present minireview discusses recent advances in these domains. Key words: cancer vaccines; T cell monitoring; tetramers; immunotherapy Tumour antigensRapid advances in the identification of MHC class I-restricted tumour antigens (TA) and their antigenic peptides 1 took place at the end of the 20th century, engendering antigen (Ag)-specific immunotherapy approaches to cancer treatment. [2][3][4] In contrast, progress in the molecular identification of MHC class II restricted peptides of TA has been much slower. Although tumour-specific CD8 ϩ T-cell responses have been documented upon vaccination with MHC class I-restricted peptides, it could be shown in murine tumour models that the generation of potent and long-lasting anti-tumour immunity is improved when both MHC class I-and class II-restricted T-cell epitopes are included in tumour vaccines. [5][6][7] These observations fostered the search for TA-derived peptides that are presented by class II molecules in cancer patients and lead to the isolation of diverse CD4 ϩ T-cell clones specific for given TA, though the precise epitopes have not yet been identified in all cases. 8,9 The high number of human MHC class II alleles severely limits the applicability of many of the antigenic peptides identified thus far. An exception is the HLA-DP4 molecule. Indeed, 2 highly prevalent alleles encode its ␤ chain and their combined frequency reaches approximately 60% of the population world-wide. Two HLA-DP4-restricted tumour associated antigenic peptides have been identified thus far. 10,11 Moreover, detailed analysis of HLA-DP4 peptide binding may facilitate future searches of novel tumour antigenic peptides restricted by this frequently occurring class II MHC allele. 12 Another favourable trait is the "degenerate" DR binding of certain antigenic peptides, i.e., various TA-derived antigenic peptides have been reported to bind to diverse HLA-DR molecules. 13,14 The identification of TA-derived epitopes presented by MHC class II molecules is complicated by the lack of effective screening methods. Recently, by combination of a computer-based algorithm for MHC-binding with T-cell functional analyses, a class II-restricted epitope of carcinoembryonic Ag (CEA, aa 116 -140) was identified that is naturally proce...

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Maintenance of memory CD8 T cells: Divided over division

2017

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Once generated during an infection, memory CD8+ T cells can provide long-lasting protection against reinfection with an intracellular pathogen, but the longevity of this defense depends on the ability of these pathogen-specific memory cells to be maintained. Figure 1. Siracusa et al. [13] show that in the spleen, CD8 memory T cells are rapidly depleted upon CyP treatment, as they undergo homeostatic proliferation. In contrast, CD8 memory T cells in the BM are mostly quiescent, and thus protected from immediate depletion by CyP. These differences could be due to the supporting cell types that are present in spleen and bone marrow (e.g, more dendritic cells in the spleen), and/or differential expression of homeostatic cytokines.which are rapidly killed by CyP treatment (Fig. 1). Importantly, by treating mice with the drug FTY720, which inhibits egress of lymphocytes from lymphoid organs, the authors demonstrate that maintenance of memory CD8 T cells in the BM upon CyP treatment is not caused by a compensatory influx of peripheral CD8 T cells. A caveat of the study is that CyP also has some non-specific side-effects: CyP can deplete proliferating Tregs that in turn affect T cell homeostasis [15], and CyP has been shown to induce type 1 interferon and thereby increase proliferation of CD8 + memory T cells [16]. Nevertheless, the findings of Siracusa et al.[13] challenge our view on how memory CD8 T cells are maintained and suggest that the underlying mechanism may differ per organ. The conclusion that CD8 memory T cells in the BM are quiescent and do not proliferate, opposes previous studies from other groups regarding the maintenance of CD8 memory T cells in the BM. The group of Francesca di Rosa has published two papers showing that BM CD8 memory T cells contain a higher percentage of proliferating cells than their counterparts in either the spleen or lymph nodes, and this group proposed that the BM acts as a niche for antigen-independent proliferation of CD8 memory T cells [17,18]. Two other studies, of which one was in non-human primates, came to the same conclusion that homeostatic proliferation of memory CD8 T cells is most profound in the BM [12,19]. The discrepancies between the results of the Radbruch group and other groups regarding the proliferation of CD8 memory T cells in the BM remain unresolved, and could be due to many different factors. One key issue is the suspected induction of proliferation by BrdU treatment [10,18]. Most studies that have claimed higher proliferation of CD8 memory T cells in the BM as compared to the spleen, have done so based on BrdU incorporation by CD8 memory T cells [12,17,18]. In their 2015 study, Radbruch and colleagues showed that a 3 day treatment of 1 mg/mL BrdU in drinking water supplemented with sugar (which increases water consumption [20]) is sufficient to induce CD8 memory T-cell proliferation, with up to 75% of all CD8 memory T cells in the BM and spleen proliferating [10]. Of note, these percentages were much higher than those reported by the aforementioned stud...

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Rapid turnover of T cells in acute infectious mononucleosis

Cited by 40 publications

References 33 publications

In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection

In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection

Recent advances in tumour antigen‐specific therapy: In vivo veritas

Maintenance of memory CD8 T cells: Divided over division

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