TY - JOUR
T1 - Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity
AU - Fanti, Silvia
AU - Stephenson, Edward
AU - Rocha-Vieira, Etel
AU - Protonotarios, Alexandros
AU - Kanoni, Stavroula
AU - Shahaj, Eriomina
AU - Paula Longhi, M
AU - Vyas, Vishal S
AU - Dyer, Carlene
AU - Pontarini, Elena
AU - Asimaki, Angeliki
AU - Bueno-Beti, Carlos
AU - De Gaspari, Monica
AU - Rizzo, Stefania
AU - Basso, Cristina
AU - Bombardieri, Michele
AU - Coe, David
AU - Wang, Guosu
AU - Harding, Daniel
AU - Gallagher, Iain
AU - Solito, Egle
AU - Elliott, Perry
AU - Heymans, Stephane
AU - Sikking, Maurits
AU - Savvatis, Konstantinos
AU - Mohiddin, Saidi A
AU - Marelli-Berg, Federica M
N1 - Funding Information:
The authors thank the patients and healthy blood donors. This work forms part of the research areas contributing to the translational research portfolio of the Cardiovascular Biomedical Research Unit at Barts, which is supported and funded by the National Institute for Health Research.
Funding Information:
This work was supported by the British Heart Foundation (grant FS/16/18/31973 to Drs E. Stephenson‚ Marelli-Berg, and Mohiddin; grant FS/18/82/34024 to Drs Protonotarios and Elliott; grant PG/18/27/33616 to Dr Asimaki; grant CH/15/2/32064 and British Heart Foundation Accelerator Award AA/18/5/34222 to Dr Marelli-Berg), the Barts’ Charity (grant MRC0230 to Drs E. Stephenson‚ Marelli-Berg, and Mohiddin), and donations from the Thompson, Hughes, and Parsons Foundations. Dr Rocha-Vieira was the recipient of a Brazilian National Council for Scientific and Technological Development Fellowship (CNPq- 20813/2017-5).
Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/12/20
Y1 - 2022/12/20
N2 - BACKGROUND: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met+) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans.METHODS: In-depth phenotyping of peripheral blood T cells, including c-Met+ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation.RESULTS: We show that c-Met+ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met+ T cells are distinct from those of c-Met-negative (c-Met-) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met+ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met+ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met+ T cells.CONCLUSIONS: Our study demonstrates that the detection of circulating c-Met+ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury.
AB - BACKGROUND: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met+) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans.METHODS: In-depth phenotyping of peripheral blood T cells, including c-Met+ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation.RESULTS: We show that c-Met+ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met+ T cells are distinct from those of c-Met-negative (c-Met-) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met+ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met+ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met+ T cells.CONCLUSIONS: Our study demonstrates that the detection of circulating c-Met+ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury.
U2 - 10.1161/CIRCULATIONAHA.121.055610
DO - 10.1161/CIRCULATIONAHA.121.055610
M3 - Article
C2 - 36417924
SN - 0009-7322
VL - 146
SP - 1930
EP - 1945
JO - Circulation
JF - Circulation
IS - 25
ER -