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Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs
from Long-term Belatacept-Treated Kidney Transplant Patients
#MMPMID28316600
Alvarez Salazar EK
; Cortés-Hernández A
; Alemán-Muench GR
; Alberú J
; Rodríguez-Aguilera JR
; Recillas-Targa F
; Chagoya de Sánchez V
; Cuevas E
; Mancilla-Urrea E
; Pérez García M
; Mondragón-Ramírez G
; Vilatobá M
; Bostock I
; Hernández-Méndez E
; De Rungs D
; García-Zepeda EA
; Soldevila G
Front Immunol
2017[]; 8
(?): 219
PMID28316600
show ga
Regulatory T cells (Tregs) are considered key players in the prevention of
allograft rejection in transplanted patients. Belatacept (BLT) is an effective
alternative to calcineurin inhibitors that appears to preserve graft survival and
function; however, the impact of this drug in the homeostasis of Tregs in
transplanted patients remains controversial. Here, we analyzed the phenotype,
function, and the epigenetic status of the Treg-specific demethylated region
(TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients
under BLT or Cyclosporine A treatment. We found a significant reduction in the
proportion of CD4(+)CD25(hi)CD127(lo/-)FOXP3(+) T cells in all patients compared
to healthy individual (controls). Interestingly, only BLT-treated patients
displayed an enrichment of the CD45RA(+) "naïve" Tregs, while the expression of
Helios, a marker used to identify stable FOXP3(+) thymic Tregs remained
unaffected. Functional analysis demonstrated that Tregs from transplanted
patients displayed a significant reduction in their suppressive capacity compared
to Tregs from controls, which is associated with decreased levels of FOXP3 and
CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT
treatment results in methylation of CpG islands within the TSDR, which could be
associated with the impaired Treg suppression function. Our data indicate that
analysis of circulating Tregs cannot be used as a marker for assessing tolerance
toward the allograft in long-term kidney transplant patients. Trial registration
number IM103008.