Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease.While the role of B cells and antibodies has been extensively investigated in the past,the advent of immune-checkpoint inh...Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease.While the role of B cells and antibodies has been extensively investigated in the past,the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology.However,it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis.Here,we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen.We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation,combining hallmarks of activation and T cell dysfunction.While circulating memory T cells rapidly disappeared,tissue-resident memory T cells emerged and persisted within the kidney,orchestrating immune-mediated nephritis.Notably,T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency.This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man.Consequently,targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.展开更多
基金supported by grants from the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),Project-ID 431984000-CRC 1453 to FA,CS,and YT,Project-ID 256073931-CRC 1160 to S,CS,and YT,Project-IDs 491676693-TRR359,and 322977937-GRK 2344 to S,Project-IDs 241702976,438496892,501370692,and 386793560-CRU 329 to CS,the Else Kröner-Fresenius-Stiftung(2016_Kolleg.03),Bad Homburg,Germany to FA,the Berta-Ottenstein-Programme for Clinician Scientists,Faculty of Medicine,University of Freiburg,Germany to FA,the Research Commission of the Faculty of Medicine,University of Freiburg,Germany to FA,the MOTI-VATE Doctoral College,Faculty of Medicine,University of Freiburg,Germany to LK,the Wilhelm Sander-Stiftung(Wilhelm Sander Foundation)to CS.The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.Open Access funding enabled and organized by Projekt DEAL.
文摘Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease.While the role of B cells and antibodies has been extensively investigated in the past,the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology.However,it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis.Here,we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen.We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation,combining hallmarks of activation and T cell dysfunction.While circulating memory T cells rapidly disappeared,tissue-resident memory T cells emerged and persisted within the kidney,orchestrating immune-mediated nephritis.Notably,T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency.This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man.Consequently,targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.
