Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis
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Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis. / Zarak-Crnkovic, Martina; Kania, Gabriela; Jaźwa-Kusior, Agnieszka; Czepiel, Marcin; Wijnen, Winandus J; Czyż, Jarosław; Müller-Edenborn, Björn; Vdovenko, Daria; Lindner, Diana; Gil-Cruz, Cristina; Bachmann, Marta; Westermann, Dirk; Ludewig, Burkhard; Distler, Oliver; Lüscher, Thomas F; Klingel, Karin; Eriksson, Urs; Błyszczuk, Przemysław.
in: BASIC RES CARDIOL, Jahrgang 115, Nr. 1, 20.12.2019, S. 6.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis
AU - Zarak-Crnkovic, Martina
AU - Kania, Gabriela
AU - Jaźwa-Kusior, Agnieszka
AU - Czepiel, Marcin
AU - Wijnen, Winandus J
AU - Czyż, Jarosław
AU - Müller-Edenborn, Björn
AU - Vdovenko, Daria
AU - Lindner, Diana
AU - Gil-Cruz, Cristina
AU - Bachmann, Marta
AU - Westermann, Dirk
AU - Ludewig, Burkhard
AU - Distler, Oliver
AU - Lüscher, Thomas F
AU - Klingel, Karin
AU - Eriksson, Urs
AU - Błyszczuk, Przemysław
PY - 2019/12/20
Y1 - 2019/12/20
N2 - Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.
AB - Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.
KW - Animals
KW - Autoimmune Diseases/immunology
KW - CD4-Positive T-Lymphocytes/physiology
KW - Fibrosis/immunology
KW - Humans
KW - Mice
KW - Myocarditis/immunology
KW - Myocardium/immunology
U2 - 10.1007/s00395-019-0766-6
DO - 10.1007/s00395-019-0766-6
M3 - SCORING: Journal article
C2 - 31863205
VL - 115
SP - 6
JO - BASIC RES CARDIOL
JF - BASIC RES CARDIOL
SN - 0300-8428
IS - 1
ER -