Experimental autoimmune encephalomyelitis (EAE) is influenced by polymorphism of the MHC. We have previously found that Lewis rats with certain MHC haplotypes are susceptible to disease induced with the myelin basic protein (MBP) peptide 63-88, whereas Lewis rats with other MHC haplotypes are resistant. Interestingly, rats with the MHC u haplotype develop an immune response to the MBP 63-88, but do not get EAE. In this study we have used intra-MHC recombinant rat strains to compare the influences of the MHC u with the a haplotype. We discovered the following: 1) The class II region of the MHC a haplotype permits EAE and a Th1 type of immune response as measured by IFN-gamma production after in vitro challenge of in vivo-primed T cells with MBP 63-88. 2) The class II region of the u haplotype is associated with a disease-protective immune response characterized by production of not only IFN-gamma, but also of IL-4 mRNA expression by the MBP 63-88-activated cells. 3) The class I region upstream of the class II region of the u haplotype is associated with a disease-protective effect and the expression of mRNA for TGF-beta after MBP 63-88-induced activation. Thus, such a TGF-beta response occurs in all strains expressing the class I Au allele. Treatment with Abs to CD8+ cells abrogates peptide-induced TGF-beta mRNA expression, and aggravates disease in strains with the class I Au allele.