Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses

Dykema, Arbor G.; Zhang, Boyang; Woldemeskel, Bezawit A.; Garliss, Caroline C.; Cheung, Laurene S.; Choudhury, Dilshad M.; Zhang, Jiajia; Aparicio, Luís M. Antón; Bom, Sadhana; Rashid, Rufiaat; Caushi, Justina X.; Hsiue, Emily Han‐Chung; Cascino, Katherine; Thompson, Elizabeth A.; Kwaa, Abena K.; Singh, Douglas A.; Thapa, Sampriti; Ordoñez, Alvaro A.; Pekosz, Andrew; D’Alessio, Franco R.; Powell, Jonathan D.; Yegnasubramanian, Srinivasan; Zhou, Shibin; Pardoll, Drew M.; Ji, Hongkai; Cox, Andrea L.; Blankson, Joel N.; Smith, Kellie N.

doi:10.1172/jci146922

Cited by 79 publications

(96 citation statements)

References 48 publications

(55 reference statements)

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“…Ten MANA-specific clonotypes, for which the TCRα could be confidently identified from the single-cell analysis, were selected for validation of MANA recognition via TCR cloning and introduction into a Jurkat-NFAT luciferase reporter system 15 . Seventy per cent of tested clonotypes (representing 95.2% of total cells bearing TCRs identified by MANAFEST) were validated as MANA-specific (Extended Data Fig.…”

Section: Expression Programs Of Mana-specific Tilmentioning

confidence: 99%

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Caushi

Zhang

et al. 2021

Nature

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297

220

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PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

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Section: Expression Programs Of Mana-specific Tilmentioning

confidence: 99%

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Caushi

Zhang

et al. 2021

Nature

Self Cite

297

220

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“…Fifth, serial determinations may have provided more accurate information on the T-cell responses elicited by the vaccine across comparison groups. Sixth, no attempt was made to differentiate between truly SARS-CoV-2-specific and cross-reactive T cells [22,23]. Seventh, further sample dilutions to precisely measure antibody levels in some participants was not performed.…”

Section: Discussionmentioning

confidence: 99%

B- and T-cell immune responses elicited by the Comirnaty® COVID-19 vaccine in nursing-home residents

Torres

Albert

Giménez

et al. 2021

Clinical Microbiology and Infection

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Objectives: The immunogenicity of the Comirnaty® vaccine against coronavirus disease 2019 (COVID-19) has not been adequately studied in elderly people with comorbidities. We assessed antibody and T-cell responses targeted to the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following full vaccination in nursing-home residents. Methods: Sixty nursing-home residents (44 female, age 53e100 years), of whom ten had previously been diagnosed with COVID-19, and 18 healthy controls (15 female, age 27e54 years) were recruited. Pre-and post-vaccination blood specimens were available for quantification of total antibodies binding the SARS-CoV-2 S protein and for enumeration of SARS-CoV-2 S-reactive IFN-g CD4 þ and CD8 þ T cells by flow cytometry. Results: The seroconversion rate in (presumably) SARS-CoV-2-naïve nursing-home residents (41/43, 95.3%) was similar to that in controls (17/18, 94.4%). A booster effect was documented in post-vaccination samples of nursing-home residents with prior COVID-19. Plasma antibody levels were higher (p < 0.01) in recovered nursing-home residents (all 2500 IU/mL) than in individuals across the other two groups (median 1120 IU/mL in naïve nursing-home residents and 2211 IU/ml in controls). A large percentage of nursing-home residents had SARS-CoV-2 S-reactive IFN-g CD8 þ (naïve 31/49, 63.2%; recovered 8/10, 80%) or CD4 þ T cells (naïve 35/49, 71.4%; recovered 7/10, 70%) at baseline, in contrast to healthy controls (3/17, 17.6% and 5/17, 29%, respectively). SARS-CoV-2 IFN-g CD8 þ and CD4 þ T-cell responses were documented in 88% (15/17) and all control subjects after vaccination, respectively, but only in 65.5% (38/ 58) and 22.4% (13/58) of nursing-home residents. Overall, the median frequency of SARS-CoV-2 IFN-g CD8 þ and CD4 þ T cells in nursing-home residents decreased in post-vaccination specimens, whereas it increased in controls. Conclusion:The Comirnaty COVID-19 vaccine elicits robust SARS-CoV-2 S antibody responses in nursinghome residents. Nevertheless, the rate and frequency of detectable SARS-CoV-2 IFN-g T-cell responses after vaccination was lower in nursing-home residents than in controls.

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“…Moreover, CCC/SARS-CoV-2-cross-reactive T cell clones shared among convalescent and infected individuals harbored lower functional avidity than non-cross-reactive clones, suggesting antigenic imprinting of the TCR repertoire by previous exposure to CCC [25,82].…”

Section: Discussionmentioning

confidence: 99%

The polarity and specificity of SARS-CoV2-specific T lymphocyte responses determine disease susceptibility

Fahrner¹,

Carrier²,

Sousa³

et al. 2021

Preprint

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Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.

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Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses

Cited by 79 publications

References 48 publications

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

B- and T-cell immune responses elicited by the Comirnaty® COVID-19 vaccine in nursing-home residents

The polarity and specificity of SARS-CoV2-specific T lymphocyte responses determine disease susceptibility

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