Tr1 Cells Emerge and Suppress Effector Th17 Cells in Glomerulonephritis
Author:
Soukou-Wargalla Shiwa12, Kilian Christoph12ORCID, Velasquez Lis N.12ORCID, Machicote Andres12, Letz Philine12ORCID, Tran Huu Ban12, Domanig Saskia12, Bertram Franziska12ORCID, Stumme Friederike12, Bedke Tanja12, Giannou Anastasios123ORCID, Kempski Jan12, Sabihi Morsal12ORCID, Song Ning24ORCID, Paust Hans-Joachim24ORCID, Borchers Alina24, Garcia Perez Laura1, Pelczar Penelope12ORCID, Liu Beibei12, Ergen Can12ORCID, Steglich Babett12, Muscate Franziska23, Huber Tobias B.4, Panzer Ulf34, Gagliani Nicola123, Krebs Christian F.24ORCID, Huber Samuel12ORCID
Affiliation:
1. *I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2. †Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 3. ‡Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4. §III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Abstract
Abstract
T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, and high expression of IL-10, CD49b, and LAG-3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis (GN), the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and, moreover, whether they exhibit regulatory function during GN have not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic GN and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10–producing CD4+ T cells infiltrate the kidneys during GN progression. Using single-cell RNA sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic GN in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with antineutrophil cytoplasmic autoantibody–associated GN and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, such as T-cell therapy. Thus, our study provides proof of concept for Tr1 cell–based therapies in experimental GN.
Funder
Deutsche Forschungsgemeinschaft
Publisher
The American Association of Immunologists
Subject
Immunology,Immunology and Allergy
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