Patients with renal failure have a pERK-dependent defective TCR-mediated activation of CD4+ T cells
L. Huang, N.H.R. Litjens, N.M. Kannegieter, M. Klepper, C.C. Baan, M.G.H. Betjes
Chair(s): Dr. Junior M. Lardy
Thursday 9 march 2017
13:00 - 13:15h
Categories: Poster - Basaal
Parallel session: Postersessie XV - Basaal 3
Phenotype and functional aspects of circulating T cells in end-stage renal disease (ESRD) patients resemble that in old healthy individuals (HI). Phosphorylation of extracellular signal-regulated kinase (pERK) is a crucial regulator in augmenting TCR-mediated activation, survival and proliferation of T cells. In naïve CD4+ T cells of HI, an age-associated decline in pERK-levels is observed caused by increased levels of dual specific phosphatase (DUSP) 6, a cytoplasmic phosphatase with substrate specificity to dephosphorylate pERK. Whether the DUSP6/pERK-dependent signaling is affected in ESRD patients is not known. The aim of this study was to assess TCR-mediated induction of pERK and the effect of the DUSP6-inhibitor BCI on pERK-levels in ESRD patients.
PBMCs of young (65 years) ESRD patients (N=24) and age-matched HI (N=24) were pre-incubated with or without BCI prior to stimulation with CD3/CD28 antibodies. Subsequently, median fluorescence intensity (MFI) of pERK was assessed for the different T-cell subsets by flow-cytometry.
An age-associated decline in TCR-induced pERK-levels was observed in the different CD4+ ( CD4+ young 658 vs elderly 535, 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. Differentiation of T cells was associated with a decline in TCR-induced pERK-levels as levels declined when comparing naive to the more differentiated memory CD4+ T cells. Inhibition of DUSP6 significantly increased TCR-induced pERK-levels of CD4+ T cells in young and elderly ESRD patients, as well as in elderly HI.
Young ESRD patients have an impaired TCR-mediated induction of pERK-levels indicative of premature T cell ageing. A DUSP6-inhibitor is a potential tool to increase TCR-induced activation of CD4+ T-cells in the ESRD patients.
