High-resolution profiling of MHC II peptide presentation capacity reveals SARS-CoV-2 CD4 T cell targets and mechanisms of immune escape

Abstract

Understanding peptide presentation by specific MHC alleles is fundamental for controlling physiological functions of T cells and harnessing them for therapeutic use. However, commonly used in silico predictions and mass spectroscopy have their limitations in precision, sensitivity, and throughput, particularly for MHC class II. Here, we present MEDi, a novel mammalian epitope display that allows an unbiased, affordable, high-resolution mapping of MHC peptide presentation capacity. Our platform provides a detailed picture by testing every antigen-derived peptide and is scalable to all the MHC II alleles. Given the urgent need to understand immune evasion for formulating effective responses to threats such as SARS-CoV-2, we provide a comprehensive analysis of the presentability of all SARS-CoV-2 peptides in the context of several HLA class II alleles. We show that several mutations arising in viral strains expanding globally resulted in reduced peptide presentability by multiple HLA class II alleles, while some increased it, suggesting alteration of MHC II presentation landscapes as a possible immune escape mechanism.

Tracing the cell-type-specific modules of immune responses during COVID-19 progression using scDisProcema

“…SARS-CoV-2 induces cytokine storm, impels interferon response, and inhibits the function of MHC class I and II molecules [40] . The alteration of MHC II presentation might further contribute to immune escape [41] . This was consistent with the downregulation of the brown module in SP.…”

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

“…The ability to activate CD4+ T cells is restricted to antigen-presenting cells that are endocytosed and processed in lysosomes for presentation on MHC class II molecules, which can transduce signals required for B-cell activation. Moreover, MHC class II antigen presentation by B lymphocytes is a multistep process involving in the presentation of MHC II-peptide complexes to CD4+ T cells (44)(45)(46)(47). Although the host's innate immune system works against the virus particles in this process, a small number of viruses still escape, and the RNAs released by these viruses are captured and identified by toll-like receptors (TLRs).…”

A high-throughput yeast display approach to profile pathogen proteomes for MHC-II binding

“…A wave of higher throughput approaches have been recently developed for studying peptide-MHC interactions, including yeast display ( Jiang and Boder, 2010 ; Liu et al, 2021a ; Rappazzo et al, 2020 ; Wen et al, 2008 ) and mammalian display-based methods ( Obermair et al, 2022 ). Many of these assays rely upon construction of DNA-based libraries ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Rappazzo et al, 2020 ; Wen et al, 2008 ), although approaches using chemically synthesized peptides have also recently been described ( Liu et al, 2021a ; Smith et al, 2019 ). DNA libraries have been generated either via DNA oligonucleotide synthesis ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Rappazzo et al, 2020 ) or random fragmentation and insertion of viral genomic material ( Wen et al, 2008 ).…”

“…Many of these assays rely upon construction of DNA-based libraries ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Rappazzo et al, 2020 ; Wen et al, 2008 ), although approaches using chemically synthesized peptides have also recently been described ( Liu et al, 2021a ; Smith et al, 2019 ). DNA libraries have been generated either via DNA oligonucleotide synthesis ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Rappazzo et al, 2020 ) or random fragmentation and insertion of viral genomic material ( Wen et al, 2008 ). Upon assembly of the peptide libraries, peptide stabilization and surface expression ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Wen et al, 2008 ) or peptide dissociation ( Rappazzo et al, 2020 ) were used to assess peptide-MHC binding.…”

“…DNA libraries have been generated either via DNA oligonucleotide synthesis ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Rappazzo et al, 2020 ) or random fragmentation and insertion of viral genomic material ( Wen et al, 2008 ). Upon assembly of the peptide libraries, peptide stabilization and surface expression ( Jiang and Boder, 2010 ; Obermair et al, 2022 ; Wen et al, 2008 ) or peptide dissociation ( Rappazzo et al, 2020 ) were used to assess peptide-MHC binding.…”