The ultimate mix and match: making sense of HLA alleles and peptide repertoires

Human leukocyte antigens class I (HLAIs) display protein fragments (~9–13 amino acid peptides primarily generated by proteasomal cleavage of cytosolic proteins) at the cell surface to the adaptive immune system (principally CD8+ T cells). If CD8+ T cells recognize these presented protein fragments, they have the ability to destroy the contaminated cell. HLAIs represent one of the most diverse set of alleles in the human genome, probably an evolutionary safeguard that ensures comprehensive immune disease coverage across the human population. Thus, it is not surprising that particular HLAI alleles are genetically associated with susceptibility to, or protection against, a number of diseases including; HIV-1, type 1 diabetes and ankolysing spondylitis. However, the diversity of the HLAI system represents a major challenge for generating cross-population peptide vaccines that bind promiscuously to different HLAIs, as well as predicting organ rejection during transplantation. In this issue of Immunology and Cell Biology, Mukherjee et al.1 have developed a new computational method and tools to decipher this complex system and improve our understanding of HLAI-mediated immune responses.