Tr1 Cells Emerge and Suppress Effector Th17 Cells in Glomerulonephritis

TY - JOUR

T1 - Tr1 Cells Emerge and Suppress Effector Th17 Cells in Glomerulonephritis

AU - Soukou-Wargalla, Shiwa

AU - Kilian, Christoph

AU - Velasquez, Lis N

AU - Machicote, Andres

AU - Letz, Philine

AU - Tran, Huu Ban

AU - Domanig, Saskia

AU - Bertram, Franziska

AU - Stumme, Friederike

AU - Bedke, Tanja

AU - Giannou, Anastasios

AU - Kempski, Jan

AU - Sabihi, Morsal

AU - Song, Ning

AU - Paust, Hans-Joachim

AU - Borchers, Alina

AU - Garcia Perez, Laura

AU - Pelczar, Penelope

AU - Liu, Beibei

AU - Ergen, Can

AU - Steglich, Babett

AU - Muscate, Franziska

AU - Huber, Tobias B

AU - Panzer, Ulf

AU - Gagliani, Nicola

AU - Krebs, Christian F

AU - Huber, Samuel

N1 - Copyright © 2023 by The American Association of Immunologists, Inc.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - 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.

AB - 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.

KW - Humans

KW - Mice

KW - Animals

KW - T-Lymphocytes, Regulatory

KW - Interleukin-10/metabolism

KW - Th17 Cells

KW - Glomerulonephritis

KW - Kidney/metabolism

KW - Transcription Factors/metabolism

KW - Th1 Cells

U2 - 10.4049/jimmunol.2300305

DO - 10.4049/jimmunol.2300305

M3 - SCORING: Journal article

C2 - 37850963

VL - 211

SP - 1669

EP - 1679

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 11

ER -