AUTOIMMUNITY ASSOCIATED WITH TGF-BETA-1-DEFICIENCY IN MICE IS DEPENDENT ON MHC CLASS-II ANTIGEN EXPRESSION

The progressive inflammatory process found in transforming growth fact or beta 1 (TGF-beta 1>-deficient mice is associated with several manif estations of autoimmunity, including circulating antibodies to nuclear antigens, immune complex deposition, and increased expression of both class I and class II major histocompatibility complex (MHC) antigens. The contribution of MHC class II antigens to the genesis of this phen otype has been determined by crossing the TGF-beta 1-null [TGF-beta 1( (-/-))] genotype into the MHC class II-deficient [MHC-II(-/-)] backgro und, Mice homozygous for both the TGF-beta 1 null allele and the class II null allele [TGF-beta 1((-/-));MHC-II(-/-)] are without evidence o f inflammatory infiltrates, circulating autoantibodies, or glomerular immune complex deposits, Instead, these animals exhibit extensive extr amedullary hematopoiesis with progressive splenomegaly and adenopathy, surviving only slightly longer than TGF-beta 1((-/-));MHC-II(+/+) mic e. The role of CD4(+) T cells, which are also absent in MHC class II-d eficient mice, is directly demonstrated through the administration of anti-CD4 monoclonal antibodies in class II-positive, TGF-beta 1((-/-)) mice. The observed reduction in inflammation and improved survival em phasize the significance of CD4(+) cells in the pathogenesis of the au toimmune process and suggest that the additional absence of class II a ntigens in TGF-beta 1((-/-));MHC-II(-/-) mice may contribute to their extreme myeloid metaplasia. Thus, MHC class II antigens are essential for the expression of autoimmunity in TGF-beta 1-deficient mice, and n ormally may cooperate with TGF-beta 1 to regulate hematopoiesis.