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Functional Genomics Unit, Gene Targeting Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, National Institutes of Health, Frederick, MD 21702;
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Laboratory of Cell Regulation and Carcinogenesis,
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Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
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Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
TGF-ß1 null (TGF-ß1-/-) 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-ß1-/- mice, we generated TGF-ß1-/- mice in the genetic background of ß2-microglobulin deficiency (ß2M-/-). TGF-ß1-/-;ß2M-/- mice had improved survival compared with TGF-ß1-/- mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-ß1-/- mice. In vivo depletion of CD8+ T cells in TGF-ß1-/- mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-ß1-/-;ß2M-/- mice was also lower than that in TGF-ß1-/- 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-ß1-/-;ß2M-/- mice, when compared with that in TGF-ß1-/- mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-ß1-/- mice and CD8+ T cells may have a contribution to the inflammation in TGF-ß1-/- mice.
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