Introduction

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. In addition, senescent T cells may have an altered pathway to phosphorylate p38. Whether premature immunological T cell ageing in ESRD patients is associated with impaired signaling via ERK and p38 is not known.

Methods

PBMCs of young (<45 years) and old (>65 years) ESRD patients (N=24) and age- and cytomegalovirus (CMV)-serostatus matched HI (N=24) were included. After CD3/CD28 antibodies stimulation, median fluorescence intensity (MFI) of phosphorylation ERK and p38 was assessed for the different T-cell subsets by flow-cytometry. Moreover, some PBMCs samples were pretreated with DUSP6 inhibitor prior to CD3/CD28 stimulation and then followed by pERK measurement.

Results

An age-associated decline in TCR-induced pERK-levels was observed in the different CD4⁺ (MFI of pERK in CD4⁺ T cells 658 vs. 535 for young and elderly HI, respectively P<0.05), but not CD8⁺, T-cell subsets from HI. Interestingly, pERK-levels of CD4⁺ T-cell subsets from young ESRD patients were comparable to elderly patients. pERK-levels in both young as well as old ESRD patients were similar to old HI. Increased differentiation status of T cells was associated with a decline in TCR-induced pERK and p38 phosphorylation, although TCR-induced p38 phosphorylation was not significantly affected by age and/or ESRD. 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 induction of pERK is affected in young ESRD patients consistent with the concept of premature immunological T cell ageing.

CITATION INFORMATION: Huang L, Litjens N, Kannegieter N, Klepper M, Baan C, Betjes M. Patients with Renal Failure Have a pERK-Dependent Defective TCR-Mediated Activation of CD4⁺ T Cells. Am J Transplant. 2017;17 (suppl 3).

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