Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

Abstract

Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

HLA Micropolymorphisms Strongly Affect Peptide–MHC Multimer–Based Monitoring of Antigen-Specific CD8+ T Cell Responses

“…Specifically, in work by Yu et al (26), it was shown that the HLA-B*57:01 and HLA-B*57:03 subtypes, which differ by only two amino acids, can both present the same HIV-1 Gag KF11 epitope, but with T cell recognition only being observed in the context of HLA-B*57:01. Likewise, a differential recognition of the same EBV epitope by Ag-specific T cells has been observed for three of the HLA-B*44 subtypes (27). Structural studies provide strong evidence that the effect of HLA micropolymorphisms on TCR interaction can in many cases not be predicted by peptide binding studies.…”

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

“…Typically, these involve highly related allotypes that exhibit limited sequence differences, which nevertheless often result in biologically significant changes in conformation of the peptide and/or the MHC-I molecule (2,(61)(62)(63). In contrast, despite the comparatively low level of sequence identity between Qa-1 b and HLA-E, remarkably, they present their respective peptide cargoes in a very similar manner for recognition by CD94-NKG2 receptors.…”

“…The orientation of residues Tyr 7 , Met 45 , Glu 63 , and Tyr 159 that line the deep hydrophobic cavity of the P2-binding pocket is similar between both Qa-1 b and HLA-E (Fig. 4B).…”

“…With the exception of the P4-Pro and the P6-Thr, the main chain of each peptide residue is stabilized by a direct hydrogen bond with Qa-1 b . For example, the amide group of P2-Met forms a hydrogen bond, which is conserved in most MHC-Ia structures, to the terminal carboxyl oxygen of Glu 63 , whereas Lys 66 N h forms a hydrogen bond to the P2-Met carbonyl group. The N terminus of the peptide is anchored by hydrogen bonds between the P1-Ala and the sidechain hydroxyl groups of Tyr 7 and Tyr 171 that are conserved in MHC class I-peptide structures (Figs.…”

“…4B). In HLA-E, position 66 is a Ser and also forms a stabilizing contact to P2, albeit through a bridging water molecule that contacts Glu 63 . By contrast, the hydrogen bond from Tyr 99 of Qa-1 b to the peptidyl amide of P3 is not maintained by the His 99 substitution in HLA-E (10) (Fig.…”