High-resolution profiling of MHC II peptide presentation capacity reveals SARS-CoV-2 CD4 T cell targets and mechanisms of immune escape
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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.
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SciScore for 10.1101/2021.03.02.433522: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Cells were mixed and co-cultured for 8-12 hours in a standard tissue culture medium, in the presence of 13ug/ml anti-mouse FasL antibodies (BioXcell) to inhibit induction of cell death during incubation. anti-mouse FasLsuggested: (Bio X Cell Cat# BE0319, RRID:AB_2819046)Software and Algorithms Sentences Resources Counting was done with FilemakerPro18 and all further analysis with Excel (Microsoft). Excelsuggested: NoneMEDi MA score quality threshold: MEDi MA score for a given peptide was … SciScore for 10.1101/2021.03.02.433522: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Cells were mixed and co-cultured for 8-12 hours in a standard tissue culture medium, in the presence of 13ug/ml anti-mouse FasL antibodies (BioXcell) to inhibit induction of cell death during incubation. anti-mouse FasLsuggested: (Bio X Cell Cat# BE0319, RRID:AB_2819046)Software and Algorithms Sentences Resources Counting was done with FilemakerPro18 and all further analysis with Excel (Microsoft). Excelsuggested: NoneMEDi MA score quality threshold: MEDi MA score for a given peptide was considered of good quality if at least 40 reads were collected for a peptide and the MEDi MA value had a coefficient of variation (CV=Std.Deviation/Average) lower than 0.75. MEDisuggested: (MEDI, RRID:SCR_015668)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, the competitive binding assay is an in-vitro assay with recombinant HLAs and its limitations have to be also considered. Nevertheless, it is expected that direct tethering of peptides to the HLA stabilizes low-affinity interactions. This allows testing of such potentially short-lived peptide-HLA complexes for presentation and T cell reactivity. The key question was whether MEDi selected peptides are relevant in vivo. We therefore analyzed whether immunogenic epitopes correspond to MEDi scoring peaks. Indeed, all 8 HLA class II restricted immunogenic peptides were identified by MEDi. NetMHCIIpan missed two of them, but overall performed well for the common HLA alleles used in this study. MEDi has the advantage of being easily scalable to the thousands of alleles present in man, and to describe peptide presentability by patient-specific HLA alleles for which no good training data are available. Consistently, the immunogenic spike S955-969 peptide presented by DPA1*02:02/DPB1*05:01 and N221-242 presented by DRB1*14:05, both MEDi high, were not well predicted by netMHCIIpan. Furthermore, with MEDi we can quickly provide the presentability information for any immunogenic peptide across multiple HLA alleles. This is exemplified in this study by the very immunogenic membrane protein peptide M146-165, recognized by TCR091 in the context of DRB1*11:01 and shown by MEDi to be also presentable by several other HLAs, also not predicted by netMHCIIpan. However, the information ga...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
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