Unconventional modes of peptide–HLA-I presentation change the rules of TCR engagement. Issue 1 (4th May 2022)

• Record Type: Journal Article
• Authors: Hopkins, Jade R; MacLachlan, Bruce J; Harper, Stephen; Sewell, Andrew K; Cole, David K
• Is Part Of: Discovery immunology. Volume 1:Issue 1(2022)
• Publication Date: 2022-05-04
• Subjects: T cells -- human leukocyte antigen (HLA) -- peptide presentation -- antigen recognition -- protein flexibility -- computational simulations; Immunology -- Periodicals; 571.96
• DOI: 10.1093/discim/kyac001
• Languages: English
• ISSNs: 2754-2483

Abstract

Abstract: The intracellular proteome of virtually every nucleated cell in the body is continuously presented at the cell surface via the human leukocyte antigen class I (HLA-I) antigen processing pathway. This pathway classically involves proteasomal degradation of intracellular proteins into short peptides that can be presented by HLA-I molecules for interrogation by T-cell receptors (TCRs) expressed on the surface of CD8 + T cells. During the initiation of a T-cell immune response, the TCR acts as the T cell's primary sensor, using flexible loops to mould around the surface of the pHLA-I molecule to identify foreign or dysregulated antigens. Recent findings demonstrate that pHLA-I molecules can also be highly flexible and dynamic, altering their shape according to minor polymorphisms between different HLA-I alleles, or interactions with different peptides. These flexible presentation modes have important biological consequences that can, for example, explain why some HLA-I alleles offer greater protection against HIV, or why some cancer vaccine approaches have been ineffective. This review explores how these recent findings redefine the rules for peptide presentation by HLA-I molecules and extend our understanding of the molecular mechanisms that govern TCR-mediated antigen discrimination.