Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2

Low, Jun Siong; Vaqueirinho, Daniela; Mele, Federico; Foglierini, Mathilde; Jerak, Josipa; Perotti, Michela; Jarrossay, David; Jovic, Sandra; Perez, Laurent; Cacciatore, Rosalia; Terrot, Tatiana; Pellanda, Alessandra Franzetti; Biggiogero, Maira; Garzoni, Christian; Ferrari, Paolo; Ceschi, Alessandro; Lanzavecchia, Antonio; Sallusto, Federica; Cassotta, Antonino

doi:10.1126/science.abg8985

Cited by 127 publications

(110 citation statements)

References 31 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: 59%

“…1g). As previously described, when using sensitive assays [7][8][9]11,[22][23][24][25] (such as IFN -ELISpot with 400,000 PBMC/well 10,21 used here), some SARS-CoV-2-reactive T cells were detectable in the pre-pandemic samples; however, their multispecificity was significantly lower than in the wk16 laboratory-confirmed infected samples (Fig. 1h-i; structural responses at wk16 previously reported 21 ).…”

Section: Mainmentioning

confidence: 99%

“…The latter would be favoured by pre-existing memory T cell responses with the potential to expand rapidly upon cross-recognition of early viral products of SARS-CoV-2 replication. Early T cell proliferation and TCR clonal expansion, even prior to detectable virus, has been observed during mild SARS-CoV-2 22,38 and expansion of virus-specific T cells predates antibody induction after mRNA vaccination 39 . Having found the ES group to be enriched for SARS-CoV-2-specific T cells, particularly against RTC, we therefore investigated the possibility that some of these represented expansions of pre-existing cross-reactive responses.…”

Section: Cross-reactive T Cells Targeting Conserved Polymerasementioning

confidence: 99%

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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: 59%

Section: Mainmentioning

confidence: 99%

Section: Cross-reactive T Cells Targeting Conserved Polymerasementioning

confidence: 99%

See 1 more Smart Citation

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

Swadling

Diniz

Schmidt

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…These studies, including ours, all use peptide pools to identify immunodominant epitopes. A very recent publication by Sallusto and colleagues identifies naturally processed epitopes with a focus on the receptor binding domain (RBD) [23]. The two immunodominant, naturally processed and presented epitopes they identify, S346-365 and S446-485, overlap largely with our two peptides from the same region, S89-90 (353-371) and S112-113 (445-463).…”

Section: Discussionmentioning

confidence: 99%

Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential

Verhagen

Meijden

Lang

et al. 2021

Clinical and Experimental Immunology

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Summary Since December 2019, Coronavirus disease‐19 (COVID‐19) has spread rapidly across the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID‐19 is mediated by both short‐lived neutralising antibodies and long‐lasting virus‐reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID‐19 patients with a potentially protective response to two major antigens of the SARS‐CoV‐2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus‐reactive CD4 + T cells, we were able to confirm a set of 9 immunodominant epitopes and characterise T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, by using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCRαβ sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR‐transgenic CD4 + T cell therapy of COVID‐19.

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“…This activation state can mount potent immune responses or generate functional exhaustion. At the convalescent stage, SARS-CoV-2-specific T cells generate broad and polyfunctional responses and they even occur after mild infection or in seronegative individuals [444,463].…”

Section: T Cellsmentioning

confidence: 99%

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Duerr¹,

Jimenez²,

Dittmann³

2021

Preprint

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SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped viruses with positive-stranded RNA and envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses’ structural and functional characteristics delineating their distinct strategies for efficient spread.

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Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2

Cited by 127 publications

References 31 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

Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

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