Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8<sup>+</sup> T cell repertoire upon viral exposure

Francis, Joshua M.; Leistritz-Edwards, Del; Dunn, Augustine; Tarr, Christina; Lehman, Jesse; Dempsey, Conor; Hamel, Antoine; Rayon, Violeta; Liu, Gang; Wang, Yuntong; Wille, Marcos; Durkin, Melissa; Hadley, Kane; Sheena, Aswathy; Roscoe, Benjamin P.; Ng, Mark; Rockwell, Graham N.; Manto, Margaret; Gienger, Elizabeth; Nickerson, Joshua; Moarefi, Amir H.; Noble, Michael S.; Malia, T.; Bardwell, Philip D.; Gordon, William C.; Swain, Joanna F.; Škoberne, Mojca; Sauer, Karsten; Harris, Tim; Goldrath, Ananda W.; Shalek, Alex K.; Coyle, Anthony J.; Benoist, Christophe; Pregibon, Daniel C.

doi:10.1101/2021.04.29.441258

Cited by 15 publications

(23 citation statements)

References 65 publications

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“…We observed that the PubTCR-SharedEp group is statistically enriched for carrying HLA-B*07:02, HLA-C*07:02 and HLA A*03:01, whereas the former group includes a broader set of HLAs among which HLA A*01:01 was more pronounced (Fig 5D). The enrichment of HLA-B*07:02 in the PubTCR-SharedEp group is consistent with recent work from Francis et al 15 , and these data are in agreement with their claim that CD8+ T Cell HCoV-CoV-2 cross-reactivity may be conditioned by HLA.…”

Section: Identification Of Shared and Private Immunogenic Sars-cov-2 Peptidessupporting

confidence: 92%

“…Rather, due to the high similarity between the cognate SARS-CoV-2 antigens and (predicted) HCoV presented peptides, we suggest it is plausible that these SARS-CoV-2 specific TCRs are crossreactive with HCoV peptides. Indeed, consistent with Francis et al, 15 who demonstrate preexisting memory CD8+ T cells to SPR* peptide in 80% of unexposed individuals, we found a set of public TCRs -which are observed in both convalescent and unexposed individualsrecognising this sCoV-2-HCoV peptide. In this light, we reveal candidate public TCRs and corresponding SARS-CoV-2 peptides with high similarity to HCoVs, which should be examined further for cross-reactive potential.…”

Section: Identification Of Shared and Private Immunogenic Sars-cov-2 Peptidessupporting

confidence: 91%

“…In these convalescent patients, it is unclear whether infection itself, and/or prior exposure to HCoVs are driving this subset of individuals to select for these peptides. There is conflicting evidence surrounding the existence of memory SARS-CoV-2 cross-reactive CD8+ T cells in unexposed individuals 15,16,40 , and a limitation of our work is that we could not to provide a direct link to pre-existing immunity, because from healthy donors the MIRA dataset only evaluated expanded naïve T cells and did not examine anti-viral efficacy of the responding T cells. Indeed, although we cannot determine the cause or timeframe of this selection of sCoV-2-HCoV peptides in this subset of individuals, the potential implications are interesting.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike antibodies, T cell crossreactivity to SARS-CoV-2 appears to be more prevalent. Several recent studies have reported existence of SARS-CoV-2-specific T cells in unexposed individuals [9][10][11][12][13][14][15] , although it appears that T cell cross reactivity is more pronounced in CD4 + than CD8 + T cells in these subjects. Recent studies have provided varying insights regarding the presence of pre-existing CD8+ T cell immunity to SARS-CoV-2 conferred by HCoV.…”

Section: Introductionmentioning

confidence: 99%

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HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

Buckley

Lee

Pinho

et al. 2021

Preprint

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Pre-existing T cell immunity to SARS-CoV-2 in individuals without prior exposure to SARS-CoV-2 has been reported in several studies. While emerging evidence hints toward prior exposure to common-cold human coronaviruses (HCoV), the extent of- and conditions for- cross-protective immunity between SARS-CoV-2 and HCoVs remain open. Here, by leveraging a comprehensive pool of publicly available functionally evaluated SARS-CoV-2 peptides, we report 126 immunogenic SARS-CoV-2 peptides with high sequence similarity to 285 MHC-presented target peptides from at least one of four HCoV, thus providing a map describing the landscape of SARS-CoV-2 shared and private immunogenic peptides with functionally validated T cell responses. Using this map, we show that while SARS-CoV-2 immunogenic peptides in general exhibit higher level of dissimilarity to both self-proteome and -microbiomes, there exist several SARS-CoV-2 immunogenic peptides with high similarity to various human protein coding genes, some of which have been reported to have elevated expression in severe COVID-19 patients. We then combine our map with a SARS-CoV-2-specific TCR repertoire data from COVID-19 patients and healthy controls and show that whereas the public repertoire for the majority of convalescent patients are dominated by TCRs cognate to private SARS-CoV-2 peptides, for a subset of patients, more than 50% of their public repertoires that show reactivity to SARS-CoV-2, consist of TCRs cognate to shared SARS-CoV-2-HCoV peptides. Further analyses suggest that the skewed distribution of TCRs cognate to shared and private peptides in COVID-19 patients is likely to be HLA-dependent. Finally, by utilising the global prevalence of HLA alleles, we provide 10 peptides with known cognate TCRs that are conserved across SARS-CoV-2 and multiple human coronaviruses and are predicted to be recognised by a high proportion of the global population. Overall, our work indicates the potential for HCoV-SARS-CoV-2 reactive CD8+ T cells, which is likely dependent on differences in HLA-coding genes among individuals. These findings may have important implications for COVID-19 heterogeneity and vaccine-induced immune responses as well as robustness of immunity to SARS-CoV-2 and its variants.

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Section: Identification Of Shared and Private Immunogenic Sars-cov-2 Peptidessupporting

confidence: 92%

Section: Identification Of Shared and Private Immunogenic Sars-cov-2 Peptidessupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

Buckley

Lee

Pinho

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…To delineate the T cell responses against individual HLA-I peptides in humans, we utilized a multiplexed technology combining a barcoded tetramer assay and single-cell sequencing of epitope-reactive CD8+ T cells (Figure 6E; Francis et al, 2021). Using this method, we obtained information about (1) the ex vivo frequency of CD8+ T cells reactive to each peptide in each sample; (2) the sequences of the T cell receptors (TCRs; paired a/b chains) recognizing each peptide; and (3) gene expression profiles of individual reactive CD8+ T cells.…”

Section: Out-of-frame Hla-i Peptides Elicit T Cell Responses In Humanized Hla-a2 Mice and Individuals With Covid-19mentioning

confidence: 99%

Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Weingarten-Gabbay

Klaeger

Sarkizova

et al. 2021

Cell

Self Cite

108

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T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.

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Profound Treg perturbations correlate with COVID-19 severity

Galván-Peña

Léon

Chowdhary

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

120

148

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The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19–linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.

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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

Cited by 15 publications

References 65 publications

HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Profound Treg perturbations correlate with COVID-19 severity

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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

Cited by 15 publications

References 65 publications

HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Profound Treg perturbations correlate with COVID-19 severity

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Product

Resources

About

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