Killer cell immunoglobulin receptor profile on CD4(+) CD28(-) T cells and their pathogenic role in non-dialysis-dependent and dialysis-dependent chronic kidney disease patients.

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There is a progressive increase in cardiovascular disease with declining renal function, unexplained by traditional risk factors. A CD4(+) T-cell subpopulation (CD4(+) CD28(-) ), activated by human heat-shock protein 60 (hHSP60), expands in patients with acute coronary syndrome and is associated with vascular damage. These cells exhibit cytotoxicity via expression of activating killer cell-immunoglobulin-like receptor KIR2DS2, mainly in the absence of inhibitory KIR2DL3. We investigated expansion of these cells and the pathogenic role of the KIR in non-dialysis-dependent chronic kidney disease (NDD-CKD) and end-stage haemodialysis-dependent renal disease (HD-ESRD) patients. CD4(+) CD28(-) cells were present in 27% of the NDD-CKD and HD-ESRD patients (8-11% and 10-11% of CD4(+) compartment, respectively). CD4(+) CD28(-) cells were phenotyped for KIR and DAP12 expression. Cytotoxicity was assessed by perforin and pro-inflammatory function by interferon-γ expression on CD4(+) CD28(-) clones (NDD-CKD n=97, HD-ESRD n=262). Thirty-four percent of the CD4(+) CD28(-) cells from NDD-CKD expressed KIR2DS2 compared with 56% in HD-ESRD patients (P=0·03). However, 20% of clones expressed KIR2DL3 in NDD-CKD compared with 7% in HD-ESRD patients (P=0·004). DAP12 expression in CD28(-) 2DS2(+) clones was more prevalent in HD-ESRD than NDD-CKD (92% versus 60%; P<0·001). Only 2DS2(+) 2DL3(-) DAP12(+) clones were cytotoxic in response to hHSP60. CD4(+) CD28(-) cells exhibited increased KIR2DS2, reduced KIR2DL3 and increased DAP12 expression in HD-ESRD compared with NDD-CKD patients. These findings suggest a gradual loss of expression, functionality and protective role of inhibitory KIR2DL3 as well as increased cytotoxic potential of CD4(+) C28(-) cells with progressive renal impairment. Clonal expansion of these T cells may contribute to heightened cardiovascular events in HD-ESRD.