title: Central Role of CD45RA- Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance.
abstract: The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with demethylated Foxp3 and a specific expansion of CD4(+) CD45RA(-) Foxp3(hi) memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid-induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4(+)CD45RA(-) Foxp3(hi) memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance.
authors.affiliation: Faculty of Medicine, University of Nantes, Nantes, France; French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and.
authors.forename: Faouzi
authors.initials: F
authors.lastname: Braza
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dugast
authors.affiliation: Institute of Medical Immunology and Berlin Brandenburg Center for Regenerative Therapies, Charité Medical University, Berlin, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Panov
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Chloé
authors.initials: C
authors.lastname: Paul
authors.affiliation: Institute of Medical Immunology and.
authors.forename: Katrin
authors.initials: K
authors.lastname: Vogt
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Annaick
authors.initials: A
authors.lastname: Pallier
authors.affiliation: Faculty of Medicine, University of Nantes, Nantes, France; French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Chesneau
authors.affiliation: Faculty of Medicine, University of Nantes, Nantes, France; French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baron
authors.affiliation: Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Guerif
authors.affiliation: Institute of Medical Immunology and Berlin Brandenburg Center for Regenerative Therapies, Charité Medical University, Berlin, Germany.
authors.forename: Hong
authors.initials: H
authors.lastname: Lei
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: David-Axel
authors.initials: DA
authors.lastname: Laplaud
authors.affiliation: Institute of Medical Immunology and Berlin Brandenburg Center for Regenerative Therapies, Charité Medical University, Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Degauque
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Magali
authors.initials: M
authors.lastname: Giral
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: Institute of Medical Immunology and Berlin Brandenburg Center for Regenerative Therapies, Charité Medical University, Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: French Institute of Health and Medical Research Unit 1064, Research Institute on Urology, Nephrology, and Transplantation, and Biotherapy Clinical Investigation Center, Hôtel Dieu University Hospital, Nantes, France; and sophie.brouard@univ-nantes.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D016022:Case-Control Studies; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D006801:Humans; D016030:Kidney Transplantation; D017493:Leukocyte Common Antigens; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D023001:Transplantation Tolerance / Q000276:immunology*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; C491405:TNFRSF18 protein, human; D017493:Leukocyte Common Antigens; D001081:Apyrase; C067869:CD39 antigen
keywords: immunology; kidney transplantation; pathology; tolerance