Mechanisms of IFNγ regulation of autoimmune myocarditis

A protective effect of interferon-gamma (IFN gamma) has been described in a number of models of autoimmune disease, including experimental autoimmune myocarditis (EAM). Some reports have suggested that regulation of apoptosis in autoreactive lymphocytes mediate these protective functions. We examined the potential of IFN gamma to regulate apoptotic mechanisms in detail, both in vitro and in vivo in EAM. We observed multiple apoptotic defects in caspase activity, and the expression of TNF superfamily members on CD4(+) T cells. In addition, we observed selective defects in CD4(+) T cell activation in response to antigenic stimulation. These activation and apoptotic defects were CD4(+) cell autonomous, independent of the genotype of APCs. Inhibition of nitric oxide production in vivo did not reproduce the severe form of EAM of IFN gamma-deficient mice, indicating that this pathway does not mediate the protective effect of IFN gamma. Crosswise adoptive transfer of wild type, IFN gamma(-/-), and IFN gamma R(-/-)EAM demonstrated that IFN gamma signaling was critical in CD4(+) cells, but that non-CD4(+) sources of IFN gamma production were also involved in the control of disease. Together, these data indicate multiple mechanisms of autonomous and non-autonomous CD4(+) T cell regulation mediated by IFN gamma in the control of autoimmune heart disease. (C) 2010 Elsevier Inc. All rights reserved.