β2-Microglobulin-Deficient Background Ameliorates Lethal Phenotype of the TGF-β1 Null Mouse

Abstract

Abstract TGF-β1 null (TGF-β1−/−) mice die at 3–4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-β1−/− mice, we generated TGF-β1−/− mice in the genetic background of β2-microglobulin deficiency (β2M−/−). TGF-β1−/−;β2M−/− mice had improved survival compared with TGF-β1−/− mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-β1−/− mice. In vivo depletion of CD8+ T cells in TGF-β1−/− mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-β1−/−;β2M−/− mice was also lower than that in TGF-β1−/− mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-β1−/−;β2M−/− mice, when compared with that in TGF-β1−/− mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-β1−/− mice and CD8+ T cells may have a contribution to the inflammation in TGF-β1−/− mice.