Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination.

Adil Doganay Duru,Chaithanya Madhurantakam,Tatyana Sandalova,Per-Åke Nygren,Xiao Han,Renhua Sun,Adnane Achour,Hannes Uchtenhagen,Eva B Allerbring,Kaliroi Peqini,Sara Pellegrino,Stephen J Turner,Nadir Kadri,Jesseka Chadderton

doi:10.1371/journal.ppat.1008244

Abstract

Viral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape.

Highlights

Recognition of major histocompatibility complex class I (MHC-I)-restricted viral peptides is a prerequisite for CD8+ T-cell activation, control and/or clearance of viral infections
We believe that this approach can be implemented to currently available or novel vaccination approaches to efficiently restore T cell recognition of virus escape variants to control disease progression
We have previously demonstrated that the immunogenicity of the cancer-associated H2Db-restricted antigen gp10025-33 [23] or the T cell epitope associated with impaired peptide processing (TEIPP) neo-epitope Thr4 [24,25,26] was dramatically improved following substitution of peptide position 3 to a proline (p3P)

Summary

Introduction

Recognition of major histocompatibility complex class I (MHC-I)-restricted viral peptides is a prerequisite for CD8+ T-cell activation, control and/or clearance of viral infections. Epitope mutations can impair CTL responses [5] by e.g. altering antigen processing [6, 7], reducing the overall stability of peptide/MHC complexes (pMHC) [8, 9] and/or disrupting T-cell receptor (TCR) recognition [10, 11]. The design of altered peptide ligands (APLs) that could promote such responses would represent a crucial step towards the development of efficient vaccines [16]. A conventional and sometimes successful approach to design APLs with enhanced pMHC stability and immunogenicity has been to optimize interactions between peptide anchor residues and MHC binding pockets [17,18,19]. The design of a novel generation of APLs that could promote such responses would represent a crucial step towards the development of efficient anti-viral T-cell based vaccines [22]

Methods

Results

Discussion

Conclusion