Structural insights into protection against a SARS-CoV-2 spike variant by T cell receptor diversity

Wu, Daichao; Efimov, Grigory A.; Bogolyubova, Apollinariya V.; Pierce, Brian G.; Mariuzza, Roy A.

doi:10.1016/j.jbc.2023.103035

Cited by 7 publications

(4 citation statements)

References 55 publications

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“…Crystal structures of several TCRs from COVID-19 convalescent patients bound to two spike epitope (YLQ and RLQ) presented by HLA-A2 have been reported 23 – 26 . These structures include: (1) TCR YLQ7–YLQ–HLA-A2 25 , (2) TCR YLQ36–YLQ–HLA-A2 26 , (3) TCR NR1C–YLQ–HLA-A2 24 , (4) TCR RLQ3–RLQ–HLA-A2 25 , and (5) TCR RLQ7–RLQ–HLA-A2 72 . Notably, TCRs LLL8 and YLQ7 use the same Vα gene segment, TRAV12-2, which is closely related to the TRAV12-1 gene segment used by TCRs YLQ36 and NR1C.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors

Choy,

Chen,

et al. 2023

Nat Commun

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The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8+ T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8+ T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8+ T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8+ T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8+ T cells and their proliferative response to stimulation did not decrease over one year. We identified the N222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8+ T cells revealed highly restricted Vα gene usage (TRAV12-2) with limited CDR3α motifs, supported by structural characterization of the TCR–LLL–HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8+ T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8+ T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8+ T cell responses with a restricted TCR repertoire.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors

Choy,

Chen,

et al. 2023

Nat Commun

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“…Focused structural and biophysical analyses of individual CD4 + T cell epitopes in other anti-viral immune responses, such as influenza A 22 , 23 and HIV, 24 contribute enormously to understanding the immune response. Moreover, such data have provided mechanistic understanding to viral escape—particularly in the CD8 + T cell/HLA-I axis—including escape from SARS-CoV-2 25 , 26 , 27 , 28 and HIV. 29 , 30 Given the different properties of HLA-II-peptide binding, the mechanisms of escape may not necessarily be translatable from their cytotoxic T cell counterparts.…”

Section: Introductionmentioning

confidence: 99%

Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

et al. 2023

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“…Despite the fact that much attention has been paid to the study of SARS-CoV2 recently, only a few COVID-associated TCRs have a resolved TCR-peptide-MHC structure to date (24)(25)(26)(27). Having a variety of structures with SARS-CoV-2 epitopes can aid in studying T-cell recognition of infected cells, especially since the number of known COVID-associated TCRs is constantly growing (6).The study of TCRpeptide MHC complexes is important in understanding the immune response to SARS-CoV-2 vaccinations and the viral immune evasion strategies employed by VOCs (Variants of concern).…”

Section: Introductionmentioning

confidence: 99%

Large-scale template-based structural modeling of T-cell receptors with known antigen specificity reveals complementarity features

et al. 2023

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IntroductionT-cell receptor (TCR) recognition of foreign peptides presented by the major histocompatibility complex (MHC) initiates the adaptive immune response against pathogens. While a large number of TCR sequences specific to different antigenic peptides are known to date, the structural data describing the conformation and contacting residues for TCR-peptide-MHC complexes is relatively limited. In the present study we aim to extend and analyze the set of available structures by performing highly accurate template-based modeling of these complexes using TCR sequences with known specificity. MethodsIdentification of CDR3 sequences and their further clustering, based on available spatial structures, V- and J-genes of corresponding T-cell receptors, and epitopes, was performed using the VDJdb database. Modeling of the selected CDR3 loops was conducted using a stepwise introduction of single amino acid substitutions to the template PDB structures, followed by optimization of the TCR-peptide-MHC contacting interface using the Rosetta package applications. Statistical analysis and recursive feature elimination procedures were carried out on computed energy values and properties of contacting amino acid residues between CDR3 loops and peptides, using R.ResultsUsing the set of 29 complex templates (including a template with SARS-CoV-2 antigen) and 732 specificity records, we built a database of 1585 model structures carrying substitutions in either TCRα or TCRβ chains with some models representing the result of different mutation pathways for the same final structure. This database allowed us to analyze features of amino acid contacts in TCR - peptide interfaces that govern antigen recognition preferences and interpret these interactions in terms of physicochemical properties of interacting residues.ConclusionOur results provide a methodology for creating high-quality TCR-peptide-MHC models for antigens of interest that can be utilized to predict TCR specificity.

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Structural insights into protection against a SARS-CoV-2 spike variant by T cell receptor diversity

Cited by 7 publications

References 55 publications

SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors

SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors

Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

Large-scale template-based structural modeling of T-cell receptors with known antigen specificity reveals complementarity features

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