title: Renal Operational Tolerance Is Associated With a Defect of Blood Tfh Cells That Exhibit Impaired B Cell Help.
abstract: Renal operationally tolerant patients (TOL) display a defect in B cell differentiation, with a deficiency in plasma cells. Recently described, T follicular helper (Tfh) cells play a critical role in B cell differentiation. We analyzed blood Tfh subsets in TOL and transplanted patients with stable graft function under immunosuppression (STA). We observed a reduced proportion of blood activated and highly functional Tfh subsets in TOL, without affecting Tfh absolute numbers. Functionally, Tfh cells from TOL displayed a modified gene expression profile, failed to produce interleukin-21, and were unable to induce IgG production by naive B cells. This Tfh defect is linked to a low incidence of postgraft de novo donor-specific antibody (dnDSA) immunization, suggesting that the lack of Tfh cells in TOL may induce a protolerogenic environment with reduced risk of developing dnDSA. Finally, we showed that elevated Tfh in STA precedes the occurrence of dnDSA during an alloresponse. These data provide new insights into the mechanisms of antibody response in operational tolerance. Disrupted homeostasis and impaired Tfh function in TOL could lead to a reduced risk of developing dnDSA and suggest a predictive role of blood Tfh cells on the occurrence of dnDSA in transplant recipients.
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Chenouard
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Chesneau
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: L
authors.initials: L
authors.lastname: Bui Nguyen
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Le Bot
authors.affiliation: INSERM, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Cadoux
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: E
authors.initials: E
authors.lastname: Dugast
authors.affiliation: INSERM, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.
authors.forename: C
authors.initials: C
authors.lastname: Paul
authors.affiliation: CHU de Nantes, ITUN, Nantes, France.|Laboratoire HLA, Etablissement Français du Sang Pays de la Loire, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Malard-Castagnet
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Ville
authors.affiliation: INSERM, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.|CIC Biothérapie, Nantes, France.
authors.forename: P
authors.initials: P
authors.lastname: Guérif
authors.affiliation: LabEx Transplantex, Nantes, France.|EU Consortium BIO-DrIM.
authors.forename: J-P
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: INSERM, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.|EU Consortium VISICORT.
authors.forename: N
authors.identifier: http://orcid.org/0000-0003-2990-3513
authors.initials: N
authors.lastname: Degauque
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: R
authors.initials: R
authors.lastname: Danger
authors.affiliation: INSERM, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.|CIC Biothérapie, Nantes, France.|LabEx Transplantex, Nantes, France.|EU Consortium BIO-DrIM.
authors.forename: M
authors.initials: M
authors.lastname: Giral
authors.affiliation: INSERM, Nantes, France.|CHU de Nantes, ITUN, Nantes, France.|CIC Biothérapie, Nantes, France.|LabEx Transplantex, Nantes, France.|EU Consortium BIO-DrIM.|EU Consortium VISICORT.|Immunotherapy Graft Oncology, LabEx IGO, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Brouard
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology*; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology*; D011379:Prognosis; D012307:Risk Factors; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D066027:Transplant Recipients; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D007518:Isoantibodies; D000098546:Interleukin-21
keywords: basic (laboratory) research/science; kidney transplantation/nephrology; tolerance: clinical; tolerance: mechanisms; translational research/science