|Golde, William - Bill|
Submitted to: Immunogenetics
Publication Type: Peer reviewed journal
Publication Acceptance Date: 6/20/2011
Publication Date: 7/1/2011
Citation: Pedersen, L.E., Harndahl, M.N., Rasmussen, M., Lamberth, K., Golde, W.T., Lund, O., Nielsen, M., Buus, S. 2011. Porcine major histocompatibility complex (MHC) class I molecules and analysis of their peptide-binding specificities. Immunogenetics. 63(12):821-831. Interpretive Summary: The analysis of immune responses, particularly to viral infections, historically focuses on the induction of “cellular” immunity. This refers to the response of cytotoxic T lymphocytes (CTLs) that can kill virus infected cells. A critical aspect of mammalian immune responses is that the antigen specific receptors that mediate the response have evolved to exquisitely differentiate a normal cell from a cell infected with virus, termed “self verses non-self”. The highly variable major histocompatibility complex (MHC) proteins are the determining molecules for self. These are the “transplantation” antigens that have to be matched between donors and recipients of organ transplants. These molecules scan proteins for peptides. When a peptide is derived from normal proteins of the cell and bound by MHC, the cell looks like self to the immune system. However, when the protein is derived from a virus, the cell looks foreign and triggers CTL responses. The work presented in this paper takes years of study of the human MHC molecules and applies the knowledge of peptide scanning by human MHC to swine MHC molecules. Here we show that molecules with domains derived from both human and swine behave essentially the same. Further, we can use peptide binding predictions from the large database of human MHC molecules and predict what peptides the swine proteins will bind. This now allows us to predict immune responses in pigs and use this information in the design of vaccines to prevent important viral infections like foot-and-mouth disease.
Technical Abstract: In all vertebrate animals, CD8+ cytotoxic T lymphocytes (CTLs) are controlled by major histocompatibility complex class I (MHC-I) molecules, which are highly polymorphic peptide receptors selecting and presenting endogenously derived epitopes to circulating cytotoxic lymphocytes (CTLs). The polymorphism of the MHC effectively individualizes the immune response of each member of the species. We have recently developed efficient methods to generate recombinant human leucocyte antigen class I (HLA-I), accompanying peptide binding assays and predictors, and HLA tetramers for specific CTL staining and manipulation. This has enabled a complete mapping of all HLA-I specificities (“the Human MHC Project”). Here, we hypothesize that these approaches can be applied to other species. We have systematically transferred domains of the frequently expressed swine MHC-I molecule, SLA-1*0401, onto a HLA-I molecule (HLA-A*1101) generating recombinant human/swine chimeric MHC-I molecules. In addition, we expressed the intact SLA-1*0401 molecule. Biochemical peptide-binding assays and positional scanning combinatorial peptide libraries (PSCPL) were used to analyze the peptide binding motifs of these molecules. The pan-specific predictor of peptide-MHC binding, NetMHCpan, was originally developed to interpolate the binding specificities of known HLA-I molecules and cover the specificities of unknown HLA-I molecules. This algorithm successfully predicted the specificities of the SLA-1*0401 molecule as well as the porcine/human chimeric MHC-I molecules. These data indicate that it is possible to extend the biochemical and bioinformatics tools of the Human MHC Project to other vertebrate species.