HLA-A*11:01-restricted CD8+ T cell immunity against influenza A and influenza B viruses in Indigenous and non-Indigenous people.

Jennifer R Habel ,Jane Nelson,Steve Rockman,Liyen Loh,E Bridie Clemens,Anthony W Purcell,Nicole A Mifsud,Luca Hensen,Louise C Rowntree,Katherine Kedzierska,Jane Davies,Jamie Rossjohn,Patricia T Illing,Weisan Chen,Adrian Miller,Christopher Szeto,Andrea Nguyen ,Stéphanie Gras ,Steven Y C Tong

doi:10.1371/journal.ppat.1010337

Abstract

HLA-A*11:01 is one of the most prevalent human leukocyte antigens (HLAs), especially in East Asian and Oceanian populations. It is also highly expressed in Indigenous people who are at high risk of severe influenza disease. As CD8+ T cells can provide broadly cross-reactive immunity to distinct influenza strains and subtypes, including influenza A, B and C viruses, understanding CD8+ T cell immunity to influenza viruses across prominent HLA types is needed to rationally design a universal influenza vaccine and generate protective immunity especially for high-risk populations. As only a handful of HLA-A*11:01-restricted CD8+ T cell epitopes have been described for influenza A viruses (IAVs) and epitopes for influenza B viruses (IBVs) were still unknown, we embarked on an epitope discovery study to define a CD8+ T cell landscape for HLA-A*11:01-expressing Indigenous and non-Indigenous Australian people. Using mass-spectrometry, we identified IAV- and IBV-derived peptides presented by HLA-A*11:01 during infection. 79 IAV and 57 IBV peptides were subsequently screened for immunogenicity in vitro with peripheral blood mononuclear cells from HLA-A*11:01-expressing Indigenous and non-Indigenous Australian donors. CD8+ T cell immunogenicity screening revealed two immunogenic IAV epitopes (A11/PB2320-331 and A11/PB2323-331) and the first HLA-A*11:01-restricted IBV epitopes (A11/M41-49, A11/NS1186-195 and A11/NP511-520). The immunogenic IAV- and IBV-derived peptides were >90% conserved among their respective influenza viruses. Identification of novel immunogenic HLA-A*11:01-restricted CD8+ T cell epitopes has implications for understanding how CD8+ T cell immunity is generated towards IAVs and IBVs. These findings can inform the development of rationally designed, broadly cross-reactive influenza vaccines to ensure protection from severe influenza disease in HLA-A*11:01-expressing individuals.

Highlights

Influenza viruses remain an annual epidemic human pathogen despite progress in vaccine formulation and anti-viral therapies
Killer CD8+ T cells recognising viral peptides presented by human leukocyte antigens (HLAs) class I glycoproteins can provide broad immunity across distinct influenza strains and subtypes
We identified novel CD8+ T cell targets for influenza A and influenza B viruses in the context of HLA-A 11:01, an HLA class I (HLA-I) allomorph highly prevalent in East Asia and Oceania, including Indigenous populations

Summary

Introduction

Influenza viruses remain an annual epidemic human pathogen despite progress in vaccine formulation and anti-viral therapies. Three types of influenza viruses infect humans, type A (IAV), B (IBV) and C (ICV). CD8+ T cells can confer broad cross-reactivity across all IAVs, IBVs and ICVs [9], having key implications for the design of universal vaccines that do not require annual reformulation. Vaccines eliciting cross-reactive cytotoxic CD8+ T cells could reduce annual rates of IAV and IBV-induced morbidity and mortality as well as protect children from ICV. As current influenza vaccines do not promote cytotoxic T cell memory [10], it is important to understand how to elicit protective CD8+ T cell immunity against seasonal, pandemic and recently emerged IAVs and IBVs

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