Dataset Information

PERK-dependent defective TCR-mediated activation of CD4⁺ T cells in end-stage renal disease patients.

ABSTRACT:

Background

Patients with end-stage renal disease (ESRD) have an impaired immune response with a prematurely aged T-cell system. Mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and p38, regulate diverse cellular programs by transferring extracellular signals into an intracellular response. T cell receptor (TCR)-induced phosphorylation of ERK (pERK) may show an age-associated decline, which can be reversed by inhibiting dual specific phosphatase (DUSP) 6, a cytoplasmic phosphatase with substrate specificity to dephosphorylate pERK. The aim of this study was to assess whether ESRD affects TCR-mediated signaling and explore possibilities for intervening in ESRD-associated defective T-cell mediated immunity.

Results

An age-associated decline in TCR-induced pERK-levels was observed in the different CD4⁺ (P < 0.05), but not CD8⁺, T-cell subsets from healthy individuals (HI). Interestingly, pERK-levels of CD4⁺ T-cell subsets from young ESRD patients were in between young and elderly HI. A differentiation-associated decline in TCR-induced ERK and p38 phosphorylation was observed in T cells, although TCR-induced p38 phosphorylation was not significantly affected by age and/or ESRD. Frequencies of TCR-induced CD69-expressing CD4⁺ T cells declined with age and were positively associated with pERK. In addition, an age-associated tendency of increased expression of DUSP6 was observed in CD4⁺ T cells of HI and DUSP6 expression in young ESRD patients was similar to old HI. Inhibition of DUSP6 significantly increased TCR-induced pERK-levels of CD4⁺ T cells in young and elderly ESRD patients, and elderly HI.

Conclusions

TCR-mediated phosphorylation of ERK is affected in young ESRD patients consistent with the concept of premature immunological T cell ageing. Inhibition of DUSP6 specific for pERK might be a potential intervention enhancing T-cell mediated immunity in ESRD patients.

SUBMITTER: Huang L

PROVIDER: S-EPMC5477144 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

pERK-dependent defective TCR-mediated activation of CD4<sup>+</sup> T cells in end-stage renal disease patients.

Huang Ling L Litjens Nicolle H R NHR Kannegieter Nynke M NM Klepper Mariska M Baan Carla C CC Betjes Michiel G H MGH

Immunity & ageing : I & A 20170619

<h4>Background</h4>Patients with end-stage renal disease (ESRD) have an impaired immune response with a prematurely aged T-cell system. Mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and p38, regulate diverse cellular programs by transferring extracellular signals into an intracellular response. T cell receptor (TCR)-induced phosphorylation of ERK (pERK) may show an age-associated decline, which can be reversed by inhibiting dual specific phosphat ...[more]

PMID: 28642802

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Project description:A broad T cell receptor (TCR-) repertoire is required for an effective immune response. TCR-repertoire diversity declines with age. End-stage renal disease (ESRD) patients have a prematurely aged T cell system which is associated with defective T cell-mediated immunity. Recently, we showed that ESRD may significantly skew the TCR Vβ-repertoire. Here, we assessed the impact of ESRD on the TCR Vβ-repertoire within different T cell subsets using a multiparameter flow-cytometry-based assay, controlling for effects of aging and CMV latency. Percentages of 24 different TCR Vβ-families were tested in circulating naive and memory T cell subsets of 10 ESRD patients and 10 age- and CMV-serostatus-matched healthy individuals (HI). The Gini-index, a parameter used in economics to describe the distribution of income, was calculated to determine the extent of skewing at the subset level taking into account frequencies of all 24 TCR Vβ-families. In addition, using HI as reference population, the differential impact of ESRD was assessed on clonal expansion at the level of an individual TCR Vβ-family. CD8+, but not CD4+, T cell differentiation was associated with higher Gini-TCR indices. Gini-TCR indices were already significantly higher for different CD8+ memory T cell subsets of younger ESRD patients compared to their age-matched HI. ESRD induced expansions of not one TCR Vβ-family in particular and expansions were predominantly observed within the CD8+ T cell compartment. All ESRD patients had expanded TCR Vβ-families within total CD8+ T cells and the median (IQ range) number of expanded TCR Vβ-families/patient amounted to 2 (1-4). Interestingly, ESRD also induced clonal expansions of TCR Vβ-families within naive CD8+ T cells as 8 out of 10 patients had expanded TCR Vβ-families. The median (IQ range) number of expanded families/patient amounted to 1 (1-1) within naive CD8+ T cells. In conclusion, loss of renal function skews the TCR Vβ-repertoire already in younger patients by inducing expansions of different TCR Vβ-families within the various T cell subsets, primarily affecting the CD8+ T cell compartment. This skewed TCR Vβ-repertoire may be associated with a less broad and diverse T cell-mediated immunity.

Dataset Information

PERK-dependent defective TCR-mediated activation of CD4⁺ T cells in end-stage renal disease patients.

Background

Results

Conclusions

Publications

pERK-dependent defective TCR-mediated activation of CD4<sup>+</sup> T cells in end-stage renal disease patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

PERK-dependent defective TCR-mediated activation of CD4+ T cells in end-stage renal disease patients.

Background

Results

Conclusions

Publications

pERK-dependent defective TCR-mediated activation of CD4<sup>+</sup> T cells in end-stage renal disease patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PERK-dependent defective TCR-mediated activation of CD4⁺ T cells in end-stage renal disease patients.