Abstract
The antigenic repertoire presented by MHC molecules is generated by the antigen processing and presentation (APP) pathway. We analyzed the evolutionary history of 45 genes involved in APP at the inter- and intra-species level. Results showed that 11 genes evolved adaptively in mammals. Several positively selected sites involve positions of fundamental importance to the protein function (e.g. the TAP1 peptide-binding domains, the sugar binding interface of langerin, and the CD1D trafficking signal region). In CYBB, all selected sites cluster in two loops protruding into the endosomal lumen; analysis of missense mutations responsible for chronic granulomatous disease (CGD) showed the action of different selective forces on the very same gene region, as most CGD substitutions involve aminoacid positions that are conserved in all mammals. As for ERAP2, different computational methods indicated that positive selection has driven the recurrent appearance of protein-destabilizing variants during mammalian evolution. Application of a population-genetics phylogenetics approach showed that purifying selection represented a major force acting on some APP components (e.g. immunoproteasome subunits and chaperones) and allowed identification of positive selection events in the human lineage.We also investigated the evolutionary history of APP genes in human populations by developing a new approach that uses several different tests to identify the selection target, and that integrates low-coverage whole-genome sequencing data with Sanger sequencing. This analysis revealed that 9 APP genes underwent local adaptation in human populations. Most positive selection targets are located within noncoding regions with regulatory function in myeloid cells or act as expression quantitative trait loci. Conversely, balancing selection targeted nonsynonymous variants in TAP1 and CD207 (langerin). Finally, we suggest that selected variants in PSMB10 and CD207 contribute to human phenotypes. Thus, we used evolutionary information to generate experimentally-testable hypotheses and to provide a list of sites to prioritize in follow-up analyses.
Highlights
Cell mediated immune responses are initiated by the recognition of an MHC/antigen complex on the surface of an APC by a T cell receptor (TcR)
Non-conventional T cell populations exist that express TcRs with semi-invariant a-chains: MAIT cells recognize antigens bound to the class Ib MHC molecule MR1, and iNKT cells respond to lipids and glycolipid antigens bound to CD1D
The antigenic repertoire is generated by the antigen processing and presentation pathway
Summary
Cell mediated immune responses are initiated by the recognition of an MHC/antigen complex on the surface of an APC (antigen presenting cell) by a T cell receptor (TcR). MHC class I and II molecules present peptides to T cells that express the CD8 or CD4 molecules, respectively. Non-conventional T cell populations exist that express TcRs with semi-invariant a-chains: MAIT (mucosal-associated invariant T) cells recognize antigens bound to the class Ib MHC molecule MR1, and iNKT (invariant natural killer T) cells respond to lipids and glycolipid antigens bound to CD1D. Peptides that will be embedded into the cleft of class I molecules are initially processed by the proteasome, a complex structure located in the cytoplasm. Immune cells and other cell types exposed to interferon gamma express a variant of the proteasome referred to as the immunoproteasome and differing in a few subunit components (Figure 1) [1]. The proteasome activity can be complemented in the cytosol by endopeptidases (Figure 1) [1,2]
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