Vimentin modulates regulatory T cell receptor-ligand interactions at distal pole complex, leading to dysregulated host response to viral pneumonia
Ruihua Ma,
Andrew D. Prigge,
Tatiana P. Ortiz Serrano,
Yuan Cheng,
Jennifer M. Davis,
Karen F. Lou,
Walter A. Wood,
Hanh Chi Do,
Ziyou Ren,
McKenzie M. Fulcer,
Mary J. Lotesto,
Benjamin D. Singer,
Bria M. Coates,
Karen M. Ridge
Affiliations
Ruihua Ma
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding author
Andrew D. Prigge
Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
Tatiana P. Ortiz Serrano
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Yuan Cheng
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Jennifer M. Davis
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Karen F. Lou
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Walter A. Wood
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Hanh Chi Do
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Ziyou Ren
Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
McKenzie M. Fulcer
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Mary J. Lotesto
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Benjamin D. Singer
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Bria M. Coates
Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
Karen M. Ridge
Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding author
Summary: Forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) resolve acute inflammation and repair the injured lung after viral pneumonia. Vimentin is a critical protein in the distal pole complex (DPC) of Tregs. This study reveals the inhibitory effect of vimentin on the suppressive and reparative capacity of Tregs. Treg-specific deletion of vimentin increases Helios+interleukin-18 receptor (IL-18R)+ Tregs, suppresses inflammatory immune cells, and enhances tissue repair, protecting Vimfl/flFoxp3YFP-cre mice from influenza-induced lung injury and mortality. Mechanistically, vimentin suppresses the induction of amphiregulin, an epidermal growth factor receptor (EGFR) ligand necessary for tissue repair, by sequestering IL-18R to the DPC and restricting receptor-ligand interactions. We propose that vimentin in the DPC of Tregs functions as a molecular switch, which could be targeted to regulate the immune response and enhance tissue repair in patients with severe viral pneumonia.
