HLA class-I-peptide stability mediates CD8+ Tcell immunodominance hierarchies and facilitates HLA-associated immune control of HIV.

Clarety Kaseke,Jonathan M Urbach,Ashok Khatri,Mary Carrington,Arman Bashirova,Fernando Senjobe,Rhoda Tano-Menka,Ryan J Park,Alicja Piechocka-Trocha,Wilfredo F Garcia Beltran,Overbeck C Takou Mbah,Michael T Waring,Bruce D Walker,Elizabeth J Rossin,Gaurav D Gaiha,Anusha Nathan,Dylan Koundakjian,Jiaqi Ma,Nishant K Singh,Brian M Baker,Michael E Birnbaum

doi:10.1016/j.celrep.2021.109378

Abstract

SummaryDefining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.

Highlights

CD8+ T cells play a key role in the suppression of viral infections through recognition of short viral peptides presented in complex with human leukocyte antigen (HLA) class-I glycoproteins (HLA-A, -B, and -C)
We developed a direct cell-based HLA class-I-peptide stability assay by generating a panel of mono-allelic HLA class-I cell lines and subsequently editing the transporter associated with antigen processing (TAP) 1 gene using CRISPR/Cas9
We developed and applied this assay for 18 HLA class-I alleles to demonstrate that relative HLA class-Ipeptide stability is a key feature of ID CD8+ T cell epitopes and overall ID hierarchies, as defined by the frequency of CD8+ T cell epitope targeting in HIV-infected individuals (Streeck et al, 2009)

Summary

Introduction

CD8+ T cells play a key role in the suppression of viral infections through recognition of short viral peptides presented in complex with human leukocyte antigen (HLA) class-I glycoproteins (HLA-A, -B, and -C). While individual HLA class-I alleles can present thousands of unique peptides (Hunt et al, 2007; Vita et al, 2019), and viral genomes can encode many potential immunogenic sequences, in any given infection there is a remarkable restriction of CD8+ T cell responses to a limited set of pathogen-derived epitopes. Previous work in mouse models has suggested that the ability of viral epitopes to bind and stabilize major histocompatibility complex (MHC) class-I and class-II molecules may contribute to ID hierarchies (Busch and Pamer, 1998; Chen et al, 2000; Lazarski et al, 2005; Thirdborough et al, 2008; van der Burg et al, 1996) This is less well-established in humans, where HLA class-I-peptide stability has primarily been associated with epitope immunogenicity (Assarsson et al, 2007; Harndahl et al, 2012; Rasmussen et al, 2016). A comprehensive analysis of epitope-mediated stabilization of HLA class-I molecules, for a broad set of HLA alleles and well-defined pathogens (e.g., human immunodeficiency virus [HIV]), would provide substantive insight into the contribution of surface HLA class-I-peptide stabilization to CD8+ T cell ID hierarchies

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Discussion

Conclusion