beta(2)-microglobulin-deficient background ameliorates lethal phenotype ofthe TGF-beta 1 null mouse

TGF-beta 1 null (TGF-beta 1(-/-)) mice die at 3-4 wk of age and show an aut oimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules, To determine the role of MHC class I Ags in t he autoimmune manifestations and the inflammation observed in TGF-beta 1(-/ -) mice, we generated TGF-beta 1(-/-) mice in the genetic background of bet a(2)-microglobulin deficiency (beta(2)M(-/-)). TGF-beta 1(-/-);beta(2)M(-/- ) mice had improved survival compared with TGF-beta 1(-/-) mice. Histopatho logical examination showed less severe inflammation, especially in the hear t, where Mac-2 reactive macrophages were significantly decreased as compare d with TGF-beta 1(-/-) mice. In vivo depletion of CD8(+) T cells in TGF-bet a 1(-/-) mice confirmed suppression of inflammation and reduction in the se verity of the wasting syndrome. MHC class IT mRNA expression in TGF-beta 1( -/-);beta(2)M(-/-) mice was also lower than that in TGF-beta 1(-/-) mice, s uggesting reduced systemic inflammation. Autoimmune response as judged by s erum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidne y was reduced in TGF-beta 1(-/-);beta(2)M(-/-) mice, when compared with tha t in TGF-beta 1(-/-) mice. Our data thus indicate that MHC class I molecule s influence the development of the autoimmunity and the inflammation seen i n TGF-beta 1(-/-) mice and CD8(+) T cells may have a contribution to the in flammation in TGF-beta 1(-/-) mice.