Killer cell immunoglobulin receptor profile on CD 4 + CD 28 − T cells and their pathogenic role in non‐dialysis‐dependent and dialysis‐dependent chronic kidney disease patients

Summary There is a progressive increase in cardiovascular disease with declining renal function, unexplained by traditional risk factors. A CD 4 + T‐cell subpopulation ( CD 4 +   CD 28 − ), activated by human heat‐shock protein 60 ( hHSP  60), 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 KIR 2 DS 2, mainly in the absence of inhibitory KIR 2 DL 3. 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. CD 4 +   CD 28 − cells were present in 27% of the NDD ‐ CKD and HD ‐ ESRD patients (8–11% and 10–11% of CD 4 + compartment, respectively). CD 4 +   CD 28 − cells were phenotyped for KIR and DAP 12 expression. Cytotoxicity was assessed by perforin and pro‐inflammatory function by interferon‐ γ expression on CD 4 +   CD 28 − clones ( NDD ‐ CKD n  = 97, HD ‐ ESRD n  = 262). Thirty‐four per cent of the CD 4 +   CD 28 − cells from NDD ‐ CKD expressed KIR 2 DS 2 compared with 56% in HD ‐ ESRD patients ( P  = 0·03). However, 20% of clones expressed KIR 2 DL 3 in NDD ‐ CKD compared with 7% in HD ‐ ESRD patients ( P  = 0·004). DAP 12 expression in CD 28 −  2 DS 2 + clones was more prevalent in HD ‐ ESRD than NDD ‐ CKD (92% versus 60%; P  < 0·001). Only 2 DS 2 +  2 DL 3 −   DAP 12 + clones were cytotoxic in response to hHSP  60. CD 4 +   CD 28 − cells exhibited increased KIR 2 DS 2, reduced KIR 2 DL 3 and increased DAP 12 expression in HD ‐ ESRD compared with NDD ‐ CKD patients. These findings suggest a gradual loss of expression, functionality and protective role of inhibitory KIR 2 DL 3 as well as increased cytotoxic potential of CD 4 +  C28 − cells with progressive renal impairment. Clonal expansion of these T cells may contribute to heightened cardiovascular events in HD ‐ESRD.