MHC and Transgenic Mice. A study into polymorphism and function of class I and class II molecules

Sammanfattning: Transplantation antigens encoded in the major histocompatibility complex (MHC) bind peptides and present them to T cells. We showed that mouse T cells expressing transgenic human CD8 can recognise human MHC class I. Expression on mature T cells is sufficient for activation in a mixed lymphocyte culture but expression both on thymocytes and mature T cells is necessary for peptide specific MHC restricted responses. Transgenic human MHC class I and CD8 double transgenic mice can mount an immune response to flu virus. The T cell response mounted to any given stimuli is highly dependent on MHC haplotype. While the MHC of mouse and man are rather well characterised the polymorphism in rat MHC have not been thoroughly investigated. We sequenced cDNAs for the RT1-D loci. Contrary to the human homologue HLA-DR, a single allele is common in many labororatory rat strains. Mice with the MHC class II Aq may develop arthritis after immunisation with type II collagen (CII), but Ap mice do not. Both these class II molecules can present unmodified collagen peptides but only Aq can present glycosylated forms. We compared binding of the CII peptides to class II Aq and Ap. The amino acids most important for binding class II were isoleucine in position 260 and phenylalanine in position 263. The difference between the Aq and Ap is flanking the binding site of I260. A transgene coding for the b-chain in Aq expressed in Ap mice enable them to respond to glycosylated CII peptides. However, when bred to mice with other MHC haplotypes a different pattern evolved. Only some a-chains could support cell surface expression of the transgene and none of the mice with mixed class II made a T cell response to CII. A sequence analysis of the a-chains showed replacement close to position 260 or 263 indicating a loss of peptide binding capacity as the reason for the non-responsiveness. While CD4 deficient mice still had some MHC class II restricted helper T cells the responses to glycosylated collagen peptides were diminished. MHC class II transgenic and gene deficient mice were immunised with CII and followed for development of arthritis. CD4 deficient, but not CD8 deficient, mice had a reduced incidence of the disease. C3H.NB mice transgenic for Aq developed arthritis but B10.P with the same transgene did not. After excluding effects on T cell activation and protective effects from sex hormones a transgene mediated effect on B cell function with a higher impact on B10.P mice was identified to be the likely reason for the resistance to collagen induced arthritis.