Impaired up-regulation of CD25 on CD4+ T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure

Marina Afanasyeva, Dimitrios Georgakopoulos, Diego F. Belardi, Djahida Bedja, De Lisa Fairweather, Yan Wang, Ziya Kaya, Kathleen L. Gabrielson, E. Rene Rodriguez, Patrizio Caturegli, David A. Kass, Noel R. Rose

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-γ deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-γ deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-γ knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD44high) CD3+ T cells due to reduced apoptosis of CD4+, but not CD8+, T cells. CD4+ T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD4 +CD44+CD25- T cells and their infiltration into the heart. CD4+CD25- T cells are less apoptosis-prone compared with the CD25+ population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-γ deficiency in autoimmune myocarditis is associated with preferential expansion of CD4+CD44+CD25- T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-γ KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure.

Original languageEnglish (US)
Pages (from-to)180-185
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2005

Keywords

  • Activation-induced cell death
  • Autoimmunity
  • Pressure-volume relations

ASJC Scopus subject areas

  • General

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    Afanasyeva, M., Georgakopoulos, D., Belardi, D. F., Bedja, D., Fairweather, D. L., Wang, Y., Kaya, Z., Gabrielson, K. L., Rodriguez, E. R., Caturegli, P., Kass, D. A., & Rose, N. R. (2005). Impaired up-regulation of CD25 on CD4+ T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure. Proceedings of the National Academy of Sciences of the United States of America, 102(1), 180-185. https://doi.org/10.1073/pnas.0408241102