Reduced TCR-signalling contributes to impaired Th17 responses in tolerant kidney transplant recipients

TY - JOUR

T1 - Reduced TCR-signalling contributes to impaired Th17 responses in tolerant kidney transplant recipients

AU - Nova-Lamperti, Estefania

AU - Romano, Marco

AU - Christakoudi, Sofia

AU - Runglall, Manohursingh

AU - McGregor, Reuben

AU - Mobillo, Paula

AU - Kamra, Yogesh

AU - Tsui, Tjir-Li

AU - Norris, Sonia

AU - John, Susan

AU - Boardman, Dominic A

AU - Lechler, Robert I

AU - Lombardi, Giovanna

AU - Hernandez-Fuentes, Maria P

AU - www.GAMBITstudy.co.uk

PY - 2017/9/12

Y1 - 2017/9/12

N2 - BACKGROUND: The development of spontaneous kidney transplant tolerance has been associated with numerous B cell-related immune alterations. We have previously shown that tolerant recipients exhibit reduced B cell receptor (BCR) signalling and higher IL-10 production than healthy volunteers. However, it is unclear whether CD4T cells from tolerant recipients also display an antiinflammatory profile that could contribute to graft maintenance.METHODS: CD4T cells were isolated from kidney transplant recipients who were identified as being tolerant recipients, patients with chronic-rejection or healthy volunteers. CD4T cells from the 3 groups were compared in terms of their gene expression profile, phenotype and functionally upon activation.RESULTS: Gene expression analysis of transcription factors and signalling proteins, in addition to surface proteins expression and cytokine production, revealed that tolerant recipients possessed fewer Th17 cells and exhibited reduced Th17 responses, relative to patients with chronic rejection or healthy volunteers. Furthermore, impaired TCR signalling and altered cytokine cooperation by monocytes contributed to the development of Th17 cells in tolerant recipients.CONCLUSIONS: These data suggest that defective proinflammatory Th17 responses may contribute to the prolonged graft survival and stable graft function, which is observed in tolerant recipients in the absence of immunosuppressive agents.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

AB - BACKGROUND: The development of spontaneous kidney transplant tolerance has been associated with numerous B cell-related immune alterations. We have previously shown that tolerant recipients exhibit reduced B cell receptor (BCR) signalling and higher IL-10 production than healthy volunteers. However, it is unclear whether CD4T cells from tolerant recipients also display an antiinflammatory profile that could contribute to graft maintenance.METHODS: CD4T cells were isolated from kidney transplant recipients who were identified as being tolerant recipients, patients with chronic-rejection or healthy volunteers. CD4T cells from the 3 groups were compared in terms of their gene expression profile, phenotype and functionally upon activation.RESULTS: Gene expression analysis of transcription factors and signalling proteins, in addition to surface proteins expression and cytokine production, revealed that tolerant recipients possessed fewer Th17 cells and exhibited reduced Th17 responses, relative to patients with chronic rejection or healthy volunteers. Furthermore, impaired TCR signalling and altered cytokine cooperation by monocytes contributed to the development of Th17 cells in tolerant recipients.CONCLUSIONS: These data suggest that defective proinflammatory Th17 responses may contribute to the prolonged graft survival and stable graft function, which is observed in tolerant recipients in the absence of immunosuppressive agents.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

KW - Journal Article

U2 - 10.1097/TP.0000000000001920

DO - 10.1097/TP.0000000000001920

M3 - Article

C2 - 28902773

SN - 0041-1337

JO - Transplantation

JF - Transplantation

ER -