CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses

Lineburg, Katie E.; Grant, Emma J.; Swaminathan, Srividhya; Chatzileontiadou, D.S.M.; Szeto, Christopher; Sloane, Hannah; Panikkar, Archana; Raju, Jyothy; Crooks, Pauline; Rehan, Sweera; Nguyen, Andrea; Lekieffre, Lea; Neller, Michelle A.; Tong, Zhen; Jayasinghe, Dhilshan; Chew, Keng Yih; Lobos, Christian A.; Halim, Hanim; Burrows, Jacqueline M.; Riboldi-Tunnicliffe, A.; Chen, Weisan; D’Orsogna, Lloyd; Khanna, Rajiv; Short, Kirsty R.; Smith, Corey; Gras, Stéphanie

doi:10.1016/j.immuni.2021.04.006

Cited by 151 publications

(179 citation statements)

References 47 publications

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“…3c). Pre-existing T cells had the potential to recognise all viral antigens tested, including those with less conservation across HCoV, as previously described 22,41 and responses against all these regions were further enriched in ES, suggesting many sources of pre-existing responses and de novo generated responses can contribute to T cell memory in exposed seronegative individuals. However, as with pre-pandemics samples, ES preferentially targeted NSP12 (Fig.…”

Section: Cross-reactive T Cells Targeting Conserved Polymerasesupporting

confidence: 58%

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 infection

Swadling

Diniz

Schmidt

et al. 2021

Preprint

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Individuals with likely exposure to the highly infectious SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–5. We hypothesised that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-26–12, would expand in vivo to mediate rapid viral control, potentially aborting infection. We studied T cells against the replication transcription complex (RTC) of SARS-CoV-2 since this is transcribed first in the viral life cycle13–15and should be highly conserved. We measured SARS-CoV-2-reactive T cells in a cohort of intensively monitored healthcare workers (HCW) who remained repeatedly negative by PCR, antibody binding, and neutralisation for SARS-CoV-2 (exposed seronegative, ES). 16-weeks post-recruitment, ES had memory T cells that were stronger and more multispecific than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). The postulate that HCW with the strongest RTC-specific T cells had an abortive infection was supported by a low-level increase in IFI27 transcript, a robust early innate signature of SARS-CoV-2 infection16. We showed that the RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and was preferentially targeted by T cells from UK and Singapore pre-pandemic cohorts and from ES. RTC epitope-specific T cells capable of cross-recognising HCoV variants were identified in ES. Longitudinal samples from ES and an additional validation cohort, showed pre-existing RNA-polymerase-specific T cells expanded in vivo following SARS-CoV-2 exposure, becoming enriched in the memory response of those with abortive compared to overt infection. In summary, we provide evidence of abortive seronegative SARS-CoV-2 infection with expansion of cross-reactive RTC-specific T cells, highlighting these highly conserved proteins as targets for future vaccines against endemic and emerging Coronaviridae.

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Section: Cross-reactive T Cells Targeting Conserved Polymerasesupporting

confidence: 58%

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 infection

Swadling

Diniz

Schmidt

et al. 2021

Preprint

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“…However, the role of such heterologous T cell immune responses in COVID-19 remains to be established. This can be exemplified by SARS-CoV-2-specific CD8 + T cells directed at the immunodominant HLA-B7 restricted nucleoprotein derived epitope N 105-113 (HLA-B7 N105-113 ) with a limited capacity to cross-recognize epitopes from related coronaviruses ( 23 ). Notably, the SARS-CoV-2 HLA-B7 N105-113 -restricted CD8 + T cell response is highly diverse and CD8 + T cells that specifically recognize the HLA-B7 N105-113 epitope have been shown to be present in pre-pandemic controls ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein

Chaurasia¹,

Nguyen²,

Rowntree³

et al. 2021

Journal of Biological Chemistry

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CD8 + T cells play an important role in vaccination and immunity against SARS-CoV-2 infection. Although numerous SARS-CoV-2 CD8 + T cell epitopes have been identified, the molecular basis underpinning T cell receptor (TCR) recognition of SARS-CoV-2-specific T cells remains unknown. The T cell response directed towards SARS-CoV-2 spike protein-derived S 269-277 peptide presented by the HLA-A*02:01 allomorph (hereafter the HLA-A2 S269-277 epitope) is, to date, the most immunodominant SARS-CoV-2 epitope found in individuals bearing this allele. As HLA-A2 S269-277 -specific CD8 + T cells utilize biased TRAV12 gene usage within the TCR α-chain, we sought to understand the molecular basis underpinning this TRAV12 dominance. We expressed four TRAV12 + TCRs which bound the HLA-A2 S269-277 complex with low μM affinity and determined the crystal structure of the HLA-A2 S269-277 binary complex, and subsequently a ternary structure of TRAV12 + TCR complexed to HLA-A2 S269-277 . We found that the TCR made extensive contacts along the entire length of the S 269-277 peptide, suggesting that the TRAV12 + TCRs would be sensitive to sequence variation within this epitope. To examine this, we investigated cross-reactivity towards analogous peptides from existing SARS-CoV-2 variants and closely related coronaviruses. We show via surface plasmon resonance and tetramer studies that the TRAV12 + T cell repertoire cross-reacts poorly with these analogous epitopes. Overall, we defined the structural basis underpinning biased TCR recognition of CD8 + T cells directed at an immunodominant epitope and provide a framework for understanding TCR cross-reactivity towards viral variants within the S 269-277 peptide.

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“…Immune cross-reactivity in the context of coronavirus vaccination or coronavirus infection is based on genetic conservation of antigen sequences. A recent study showed that the SARS-CoV-2 nucleocapsid protein contains highly conserved amino acid sequences 11 . In particular, the PRWYFYYLGTGPEAGLPYG sequence is nearly identical in bat coronaviruses, human coronaviruses (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…OC43), and murine coronaviruses (e.g. MHV-A59 and MHV-1) 11 . Long linear stretches of conserved amino acid sequences may facilitate the priming of cross- reactive T cell responses.…”

Section: Discussionmentioning

confidence: 99%

SARS coronavirus vaccines protect against different coronaviruses

Dangi

Palacio

Sanchez

et al. 2021

Preprint

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Although SARS-CoV-2 vaccines have shown efficacy against SARS-CoV-2, it is unclear if they can also protect against other coronaviruses that may infect humans in the future. Here, we show that SARS-CoV-2 vaccination in humans elicits cross-reactive antibodies against other coronaviruses. Our studies in mice demonstrate that SARS-CoV-2 vaccination protects against a common cold coronavirus, and that SARS-CoV-1 vaccination protects against SARS-CoV-2. Similarly, infection with a common cold coronavirus also conferred enhanced protection from subsequent infections with other coronaviruses. Mechanistically, both T cells and antibodies mediated cross-protection. This is the first direct demonstration that coronavirus-specific immunity can confer heterologous protection in vivo, providing a rationale for universal coronavirus vaccines.

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CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses

Cited by 151 publications

References 47 publications

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 infection

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 infection

Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein

SARS coronavirus vaccines protect against different coronaviruses

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