CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity

Nguyen, Thi H. O.; Rowntree, Louise C.; Petersen, Jan; Chua, Brendon Y.; Hensen, Luca; Kędzierski, Łukasz; Sandt, Carolien E. van de; Chaurasia, Priyanka; Tan, Hyon‐Xhi; Habel, Jennifer R; Zhang, Wuji; Allen, Lilith F; Earnest, Linda; Mak, Kai Yan; Juno, Jennifer A; Wragg, Kathleen; Mordant, Francesca L; Amanat, Fatima; Krammer, Florian; Mifsud, Nicole A.; Doolan, Denise L.; Flanagan, Katie L.; Sonda, Sabrina; Kaur, Jasveen; Wakim, Linda M.; Westall, Glen P.; James, Fiona; Mouhtouris, Effie; Gordon, Claire L.; Holmes, Natasha E; Smibert, Olivia C; Trubiano, Jason A; Cheng, Allen; Harcourt, Peter; Clifton, Patrick; Crawford, Jeremy Chase; Thomas, Paul G.; Wheatley, Adam K.; Kent, Stephen J.; Rossjohn, Jamie; Torresi, Joseph; Kedzierska, Katherine

doi:10.1016/j.immuni.2021.04.009

Cited by 115 publications

(203 citation statements)

References 51 publications

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“…SARS-CoV-2 reactive CD8+ T cells have been associated with milder disease 43 , and as previously mentioned, conflicting evidence has recently emerged regarding the presence of pre-existing CD8+ T cells in unexposed patients. Nguyen et al 16 ., found that SARS-CoV-2 CD8+ T cells in Australian pre-pandemic samples, including those recognising the immunodominant HLA-B*07:02-SPR* complex, predominately displayed a naïve phenotype, indicating a lack of pre-existing memory conferred by HCoV. In contrast, Francis et al 15 ., found that ~80% of unexposed individuals carrying HLA-B*07:02 show a pre-existing CD8+ T cell response to HLA-B*07:02-SPR*.…”

Section: Discussionmentioning

confidence: 98%

“…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%

“…Recent studies have provided varying insights regarding the presence of pre-existing CD8+ T cell immunity to SARS-CoV-2 conferred by HCoV. In an investigation into the immunodominant SARS-CoV-2 SPR* epitope -associated with HLA-B*07:02 -Nguyen et al 16 ., found little evidence of cross-reactive exposure in pre-pandemic Australian samples. On the other-hand, Francis et al 15 ., found evidence of pre-existing memory CD8+ T cells in naïve samples and have shown that HLA genotype conditions pre-existing CD8+ T cell memory to SARS-CoV-2, and they suggest that unexposed individuals with specific HLA alleles (such as HLA-B*07:02), may be more likely to possess cross-reactive memory T cells specific for the SPR* SARS-CoV-2 epitope.…”

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: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Staining with MHCmultimers loaded with individual peptides is an alternative approach, but it requires pre-selection of immunogenic peptides. Several immunodominant SARS-CoV-2 epitopes presented by common HLA alleles were discovered in the past year, permitting the tracking of epitope-specific T cell response in infected (Francis et al 2021;Gangaev et al 2021;Schreibing et al 2021;Shomuradova et al 2020;Kared et al 2021;Saini et al 2021;Ferretti et al 2020;Nielsen et al 2021;Peng, Yanchun et al 2020;Rha et al 2021;Sekine et al 2020;Schulien et al 2021;Habel et al 2020;Nguyen et al 2021) and vaccinated (Thimme et al 2021;Sahin et al 2021) individuals using MHC-multimers. Although at the peak of the infection response reports have described more than 10% of CD8+ T cells specific to a single SARS-CoV-2 epitope (Saini et al 2021;Gangaev et al 2021), a month after infection the frequency of most epitope-specific T cell populations is typically less than 1% (Ferretti et al 2020;Peng, Yanchun et al 2020;Kared et al 2021;Rha et al 2021).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells

Minervina

Pogorelyy

Kirk

et al. 2021

Preprint

Self Cite

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SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

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“…One of the most immunodominant CD8 epitopes identified so far is found within the SARS-CoV-2 nucleoprotein, 105-SPRWYFYYL-113 (N 105-113 ) [ 1 • , 2 • , 3 • , 4 , 5 • ]. The frequency of this epitope is potentially due to high frequency of naïve precursor T cells that can recognise this epitope [ 12 •• ]. Several other immunodominant epitopes for SARS-CoV-2 are predicted to exist.…”

Section: Introductionmentioning

confidence: 99%

Immunodominance complexity: lessons yet to be learned from dominant T cell responses to SARS-COV-2

Wellington

Yin

Kessler

et al. 2021

Current Opinion in Virology

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Immunodominance is a complex and highly debated topic of T cell biology. The current SARS-CoV-2 pandemic has provided the opportunity to profile adaptive immune responses and determine molecular factors contributing to emerging responses towards immunodominant viral epitopes. Here, we discuss parameters that alter the dynamics of CD8 viral epitope processing, generation and T-cell responses, and how immunodominance counteracts viral immune escape mechanisms that develop in the context of emerging SARS-CoV-2 variants.

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CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity

Cited by 115 publications

References 51 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

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells

Immunodominance complexity: lessons yet to be learned from dominant T cell responses to SARS-COV-2

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