Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8 + T cell repertoire upon viral exposure
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Abstract
Effective presentation of antigens by HLA class I molecules to CD8 + T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multi-omic technology to generate the first unified ex vivo characterization of the CD8 + T cell response to SARS-CoV-2 across 4 major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCR α/β sequence diversity, and the utilization of pre-existing SARS-CoV-2 reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations influence pre-existing immunity to SARS-CoV-2 and shape the immune repertoire upon subsequent viral exposure.
One-Sentence Summary
We perform a unified, multi-omic characterization of the CD8 + T cell response to SARS-CoV-2, revealing pre-existing immunity conditioned by HLA genotype.
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SciScore for 10.1101/2021.04.29.441258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
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:We acknowledge the caveat that peripheral frequencies were measured, and some degree of sequestration in viral target tissues, such as the lung, is likely to occur in acute patients. Yet, the response seems much more muted than the “all hands-on deck” …
SciScore for 10.1101/2021.04.29.441258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
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:We acknowledge the caveat that peripheral frequencies were measured, and some degree of sequestration in viral target tissues, such as the lung, is likely to occur in acute patients. Yet, the response seems much more muted than the “all hands-on deck” observed in some other viral infections (49). This meager outcome was seen both for the cross-reactive “secondary responses” by memory T cells pre-primed by endemic HCoVs, as well as for the primary responses of truly SARS-CoV-2 species-specific CD8+ T cells amplified de novo. This suggests that the paucity likely does not result from a blocking of primary activation, but from a dampening of all specific CD8+ T cells. Consistent with this notion, frequencies of influenza/EBV/CMV reactive cells were also lower in acute COVID-19 patients, compared to SARS-CoV-2 “naïve” individuals. It has been proposed that the lethal cytokine storm in severe COVID-19 stems from innate immune functions overcompensating for adaptive immune system failures (2). In this line of reasoning, one might propose that SARS-CoV-2’s noxiousness stems from a broad obstruction of antiviral CD8+ T cell responses. We have recently described a “super-Treg” phenotype in severe COVID-19, with heightened expression of FoxP3 and Treg effector molecules, akin to tumor-infiltrating Treg cells (50), and one possible interpretation is that overactive Tregs are overly suppressing these CD8+ T cells in severe COVID-19 patients. Given the widespread lymphopenia observed in a...
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.
Results from scite Reference Check: We found no unreliable references.
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