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Published online on December 20, 2004, 10.1073/pnas.0408241102
PNAS | January 4, 2005 | vol. 102 | no. 1 | 180-185


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MEDICAL SCIENCES
Impaired up-regulation of CD25 on CD4+ T cells in IFN-{gamma} knockout mice is associated with progression of myocarditis to heart failure

Marina Afanasyeva * {dagger}, Dimitrios Georgakopoulos {dagger}, {ddagger}, Diego F. Belardi {ddagger}, Djahida Bedja §, DeLisa Fairweather *, Yan Wang *, Ziya Kaya *, Kathleen L. Gabrielson §, E. Rene Rodriguez *, Patrizio Caturegli *, David A. Kass {ddagger}, and Noel R. Rose *, ¶, ||

Departments of *Pathology, {ddagger}Medicine, and §Comparative Medicine and the W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205

Communicated by John W. Littlefield, Johns Hopkins University School of Medicine, Baltimore, MD, November 5, 2004 (received for review March 8, 2004)

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-{gamma} deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-{gamma} deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-{gamma} 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-{gamma} 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-{gamma} KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure.

activation-induced cell death | autoimmunity | pressure–volume relations

Abbreviations: CM, cardiac myosin; EAM, experimental autoimmune myocarditis; KO, knockout; DCM, dilated cardiomyopathy; 7AAD, 7-aminoactinomycin D.

{dagger} M.A. and D.G. contributed equally to this work.

|| To whom correspondence should be addressed at: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building, Room 659, Baltimore, MD 21205. E-mail: nrrose{at}jhsph.edu.

© 2005 by The National Academy of Sciences of the USA


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