Broad-Based Influenza-Specific CD8+ T Cell Response without the Typical Immunodominance Hierarchy and Its Potential Implication.

Miaojuan Huang,Cristina Triffon,Rong Xu,Weisan Chen,Nicole Mifsud

doi:10.3390/v13061080

Abstract

Syngeneic murine systems have pre-fixed MHC, making them an imperfect model for investigating the impact of MHC polymorphism on immunodominance in influenza A virus (IAV) infections. To date, there are few studies focusing on MHC allelic differences and its impact on immunodominance even though it is well documented that an individual’s HLA plays a significant role in determining immunodominance hierarchy. Here, we describe a broad-based CD8+ T cell response in a healthy individual to IAV infection rather than a typical immunodominance hierarchy. We used a systematic antigen screen approach combined with epitope prediction to study such a broad CD8+ T cell response to IAV infection. We show CD8+ T cell responses to nine IAV proteins and identify their minimal epitope sequences. These epitopes are restricted to HLA-B*44:03, HLA-A*24:02 and HLA-A*33:03 and seven out of the nine epitopes are novel (NP319–330# (known and demonstrated minimal epitope positions are subscripted; otherwise, amino acid positions are shown as normal text (for example NP 319–330 or NP 313–330)), M1124–134, M27–15, NA337–346, PB239–49, HA445–453 and NS1195–203). Additionally, most of these novel epitopes are highly conserved among H1N1 and H3N2 strains that circulated in Australia and other parts of the world.

Highlights

The 1918 Spanish influenza pandemic resulted in over 50 million deaths worldwide and remains one of the deadliest plagues ever experienced in human history [1]
Combining a systematic antigen screen approach with epitope prediction, CD8+ T cell responses to nine influenza A virus (IAV) proteins (M1, M2, NP, NS1, PA, PB1, PB2, HA and NA) except for NS2 and PB1-F2 and their minimal epitope sequences were identified. These epitopes are restricted to HLA-B*44:03, HLA-A*24:02-restricted epitope NP39–47 (A*24):02 and HLA-A*33:03 and seven out of the nine epitopes are novel (NP319–330, M1124–134, M27–15, NA337–346, PB239–49, HA445–453 and NS1195–203). Most of these novel epitopes are highly conserved among strains of H1N1 and H3N2 that circulated in Australia and other parts of the world
HLA-A*24:02 was reported to be associated with severe pH1N1 disease and is an allele that is highly expressed in Indigenous Australians and Alaskans [39,40]

Summary

Introduction

The 1918 Spanish influenza pandemic resulted in over 50 million deaths worldwide and remains one of the deadliest plagues ever experienced in human history [1]. Influenza infection continues to cause epidemics and is responsible for 3–5 million severe infections and 500,000 deaths worldwide https://www.who.int/en/news-room/ fact-sheets/detail/influenza-(seasonal) (accessed on 27 April 2021), even though influenza vaccines are widely available. Most studies that investigated the underlying mechanisms of immunodominance often used syngeneic mouse models, such as the well-studied influenza A virus (IAV) infection model in C57BL/6 and BALB/c mice [11,12] Such models are well suited for studying factors such as peptide-binding ability to MHC, antigen-processing efficiency, and TCR repertoires and their impact on immunodominance [11,12,13,14,15], they are not the best means to study the impact of MHC polymorphism on immunodominance. The CD8+ T cell responses in these individuals will likely be broad and have many subdominant determinants without a typical immunodominance hierarchy; this type of response has not been previously reported for CD8+ T cells specific to IAV infections, our laboratory has previously reported such an IAV-specific CD4+ T cell response [18]

Methods

Results

Conclusion