FOXP3+ regulatory T-cells in chronic kidney disease: Molecular pathways and clinical implication

Abstract

CD4+/FOXP3+regulatoryT-cells (Tregs) areessential for the maintenanceofself-tolerance and Tregs deficiency resultsin spontaneousautoimmunity in both miceand humans.The forkheadboxP3 (FOXP3) expression is required for both survival ofTregsprecursorsas wellastheir function.Thissuggests that Tregs mayusemultiplemechanisms to limitautoimmunity and mayreflectfunctional heterogeneityamongTregs subsetsthat localize to distinct tissueenvironments. Both cellcontact- and cytokine-based immunosuppressivemechanisms would require that Tregs be in closeproximityto their targets. The fundamental regulatoryactivitythat can be consistentlydemonstratedbyTregs in vivoand in vitrohasstimulatedgreatinterest in developing novelstrategies for treatingongoinginflammatoryconditions. Patientswith end-stage kidneydisease( ESKD)areknownto displayacellularimmunedysfunction. Uremicsolutesthat accumulate during ESKD maybe involved in these processes. In these patients, oxidative stress induced by oxLDLmayincrease Tregs sensitivity to Fas-mediatedapoptosisin part as a consequence of26S proteasomeactivation. The 26Sproteasome, an ATP-dependentmultisubunit proteasecomplex found in the cytoplasmand in the nucleusof alleukaryoticcells, constitutesthe centralproteolytic machineryofthe ubiquitin/proteasomesystem. Consideringthe effectofuremiaandoxLDL,Tregs from patientswith ESKDexhibit earlycell-cycle arrestand becomeapoptotic. Thesephenomena are the consequence of the oxLDLinhibited proteasomeproteolytic activityof p27Kipi and Bax proteins in Tregs. Thismaybe one mechanisticexplanationof the cellularimmunedysfunction in patients with ESKDand mayhaveimportant implicationsin clinics, sincethis response could contribute to the micro-inflammation and atherogenesis encountered in this population. © 2009 Landes Bioscience and Springer Science+Business Media.