title: 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.
abstract: 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 (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 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 per cent 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 hHSP 60. 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.
authors.affiliation: Division of Clinical Sciences, St George's University of London, London, UK.
authors.forename: Behnam
authors.initials: B
authors.lastname: Zal
authors.forename: Nihil
authors.initials: N
authors.lastname: Chitalia
authors.forename: Yin Sing
authors.initials: YS
authors.lastname: Ng
authors.forename: Verna
authors.initials: V
authors.lastname: Trieu
authors.forename: Sana
authors.initials: S
authors.lastname: Javed
authors.forename: Rachelle
authors.initials: R
authors.lastname: Warrington
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Kaski
authors.forename: Debasish
authors.initials: D
authors.lastname: Banerjee
authors.forename: Christina
authors.initials: C
authors.lastname: Baboonian
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D054340:Receptors, KIR / Q000276:immunology*; D054344:Receptors, KIR2DL3 / Q000276:immunology*; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000276:immunology* / Q000473:pathology / Q000628:therapy*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C515078:KIR2DL3 protein, human; C433932:KIR2DS2 protein, human; D008565:Membrane Proteins; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3; C110546:TYROBP protein, human
keywords: CD4+ CD28− T cells; chronic kidney disease; killer cell immunoglobulin receptors