High resolution profiling of MHC-II peptide presentation capacity, by Mammalian Epitope Display, reveals SARS-CoV-2 targets for CD4 T cells and mechanisms of immune-escape

• Published in: bioRxiv 2021-10
• Main Authors: Obermair, Franz Josef, Renoux, Florian, Heer, Sebastian, Lee, Chloe, Cereghetti, Nastassja, Maestri, Giulia, Haldner, Yannick, Wuigk, Robin, Iosefson, Ohad, Patel, Pooja, Triebel, Katherine, Kopf, Manfred, Swain, Joanna, Kisielow, Jan
• Format: Article
• Language: English
• Subjects: Alleles; Antigen presentation; CD4 antigen; Cell recognition; COVID-19; Epitopes; Haplotypes; Histocompatibility antigen HLA; Immune evasion; Immunological synapses; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mutation; Peptides; Severe acute respiratory syndrome coronavirus 2
• DOI: 10.1101/2021.03.02.433522

Understanding the mechanisms of immune evasion is critical for formulating an effective response to global threats like SARS-CoV2. We have fully decoded the immune synapses for multiple TCRs from acute patients, including cognate peptides and the presenting HLA alleles. Furthermore, using a newly developed mammalian epitope display platform (MEDi), we determined that several mutations present in viral isolates currently expanding across the globe, resulted in reduced presentation by multiple HLA class II alleles, while some increased presentation, suggesting immune evasion based on shifting MHC-II peptide presentation landscapes. In support, we found that one of the mutations present in B1.1.7 viral strain could cause escape from CD4 T cell recognition in this way. Given the importance of understanding such mechanisms more broadly, we used MEDi to generate a comprehensive analysis of the presentability of all SARS-CoV-2 peptides in the context of multiple common HLA class II molecules. Unlike other strategies, our approach is sensitive and scalable, providing an unbiased and affordable high-resolution map of peptide presentation capacity for any MHC-II allele. Such information is essential to provide insight into T cell immunity across distinct HLA haplotypes across geographic and ethnic populations. This knowledge is critical for the development of effective T cell therapeutics not just against COVID-19, but any disease. Competing Interest Statement M.K. is an advisor to RIM. Footnotes * Typing errors corrected: Page 8: "the spike S982A mutation appeared to stabilize binding" was corrected to "the spike D118H mutation...". Figure 1D: corrected epitopes for TCRs 068 and 132 - were erroneously swapped in the previous version.