Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD.
Increased levels of oxidized low-density lipoproteins (oxLDL) contribute to the increased risk for atherosclerosis, which persists even after adjusting for traditional risk factors, among patients with ESRD. Regulatory T cells (CD4+/CD25+ Tregs), which down-regulate T cell responses to foreign and self-antigens, are protective in murine atherogenesis, but whether similar immunoregulation occurs in humans with ESRD is unknown. Because cellular defense systems against oxLDL involve proteolytic degradation, the authors investigated the role of oxLDL on proteasome activity of CD4+/CD25+ Tregs in patients with ESRD. CD4+/CD25+ Tregs isolated from uremic patients' peripheral blood, especially that of chronically hemodialyzed patients, failed to suppress cell proliferation, exhibited cell-cycle arrest, and entered apoptosis by altering proteasome activity. Treating CD4+/CD25+ Tregs with oxLDL or uremic serum ex vivo decreased the number and suppressive capacity of CD4+/CD25+ Tregs. In vitro, oxLDL promoted the accumulation of p27Kip1, the cyclin-dependent kinase inhibitor responsible for G1 cell cycle arrest, and increased apoptosis in a time- and concentration-dependent manner. In summary, proteasome inhibition by oxLDL leads to cell cycle arrest and apoptosis, dramatically affecting the number and suppressive capacity of CD4+/CD25+ Tregs in chronically hemodialyzed patients. This response may contribute to the immune dysfunction, microinflammation, and atherogenesis observed in patients with ESRD.
Meier
Pascal
P
Service of Nephrology, Centre Hospitalier Universitaire Vaudois (CHUV), 17, rue du Bugnon, 1011 Lausanne, Switzerland. pascal.meier@chuv.ch
Golshayan
Dela
D
Blanc
Edouard
E
Pascual
Manuel
M
Burnier
Michel
M
D000328:Adult; D017209:Apoptosis; D016022:Case-Control Studies; D002478:Cells, Cultured; D018920:Coculture Techniques; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000276:immunology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010835:Phytohemagglutinins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014511:Uremia / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
C494826:BAX protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D008077:Lipoproteins, LDL; D010835:Phytohemagglutinins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; C099252:oxidized low density lipoprotein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D046988:Proteasome Endopeptidase Complex