Myocardial Infarction Primes Autoreactive T Cells through Activation of Dendritic Cells.
Peripheral tolerance is crucial for avoiding activation of self-reactive T cells to tissue-restricted antigens. Sterile tissue injury can break peripheral tolerance, but it is unclear how autoreactive T cells get activated in response to self. An example of a sterile injury is myocardial infarction (MI). We hypothesized that tissue necrosis is an activator of dendritic cells (DCs), which control tolerance to self-antigens. DC subsets of a murine healthy heart consisted of IRF8-dependent conventional (c)DC1, IRF4-dependent cDC2, and monocyte-derived DCs. In steady state, cardiac self-antigen α-myosin was presented in the heart-draining mediastinal lymph node (mLN) by cDC1s, driving the proliferation of antigen-specific CD4+TCR-M T cells and their differentiation into regulatory cells (Tregs). Following MI, all DC subsets infiltrated the heart, whereas only cDCs migrated to the mLN. Here, cDC2s induced TCR-M proliferation and differentiation into interleukin-(IL)-17/interferon-(IFN)γ-producing effector cells. Thus, cardiac-specific autoreactive T cells get activated by mature DCs following myocardial infarction.
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium.
Katrien
K
Van der Borght
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Charlotte L
CL
Scott
Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
Veronika
V
Nindl
VIB Vesalius Research Center, 3000 Leuven, Belgium.
Ann
A
Bouché
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Liesbet
L
Martens
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Dorine
D
Sichien
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium.
Justine
J
Van Moorleghem
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium.
Manon
M
Vanheerswynghels
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Sofie
S
De Prijck
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Yvan
Y
Saeys
Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
Burkhard
B
Ludewig
Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium.
Thierry
T
Gillebert
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Martin
M
Guilliams
VIB Vesalius Research Center, 3000 Leuven, Belgium. Electronic address: peter.carmeliet@vib-kuleuven.be.
Peter
P
Carmeliet
Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium; Department of Pulmonary Medicine, ErasmusMC, 3015 Rotterdam, the Netherlands. Electronic address: bart.lambrecht@ugent.be.
Bart N
BN
Lambrecht
D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D009203:Myocardial Infarction / Q000276:immunology* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
D039521:CD11c Antigen; D050835:Interferon Regulatory Factors; D009218:Myosins; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8
IRF4; IRF8; autoimmunity; cardiac myosin; dendritic cell; gene expression; heart; myocardial infarction; tissue necrosis; tolerance