tetano
Editor, Senior Moderator
J Clin Invest
. 2021 Apr 8;146922.
doi: 10.1172/JCI146922. Online ahead of print.
Functional characterization of CD4+ T-cell receptors cross-reactive for SARS-CoV-2 and endemic coronaviruses
Arbor G Dykema[SUP] 1 [/SUP], Boyang Zhang[SUP] 2 [/SUP], Bezawit A Woldemeskel[SUP] 3 [/SUP], Caroline C Garliss[SUP] 3 [/SUP], Laurene S Cheung[SUP] 4 [/SUP], Dilshad Choudhury[SUP] 1 [/SUP], Jiajia Zhang[SUP] 1 [/SUP], Luis Aparicio[SUP] 1 [/SUP], Sadhana Bom[SUP] 1 [/SUP], Rufiaat Rashid[SUP] 1 [/SUP], Justina X Caushi[SUP] 1 [/SUP], Emily Han-Chung Hsiue[SUP] 1 [/SUP], Katherine Cascino[SUP] 3 [/SUP], Elizabeth A Thompson[SUP] 5 [/SUP], Abena K Kwaa[SUP] 3 [/SUP], Dipika Singh[SUP] 1 [/SUP], Sampriti Thapa[SUP] 1 [/SUP], Alvaro A Ordonez[SUP] 6 [/SUP], Andrew Pekosz[SUP] 7 [/SUP], Franco R D'Alessio[SUP] 3 [/SUP], Jonathan D Powell[SUP] 1 [/SUP], Srinivasan Yegnasubramanian[SUP] 1 [/SUP], Shibin Zhou[SUP] 5 [/SUP], Drew M Pardoll[SUP] 1 [/SUP], Hongkai Ji[SUP] 2 [/SUP], Andrea L Cox[SUP] 5 [/SUP], Joel N Blankson[SUP] 3 [/SUP], Kellie N Smith[SUP] 4 [/SUP]
Affiliations
Abstract
Background: Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to cross-recognition by T-cells specific for common cold coronaviruses (CCCs). True T-cell cross-reactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.
Methods: We used the ViraFEST platform to identify T cell responses cross-reactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC cross-reactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.
Results: Memory CD4+ T-cell clonotypes that cross-recognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Cross-reactive T-cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to mono-specific CD4+ T-cells, which was consistent with lower functional avidity of their TCRs for SARS CoV-2 relative to CCC.
Conclusions: For the first time, our data confirm the existence of unique memory CD4+ T cell clonotypes cross-recognizing SARS-CoV-2 and CCCs. The lower avidity of cross-reactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that pre-existing CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these cross-reactive T-cell responses impact clinical outcomes in COVID-19 patients.
Keywords: COVID-19; Immunology; Imprinting; MHC class 2; T cells.
. 2021 Apr 8;146922.
doi: 10.1172/JCI146922. Online ahead of print.
Functional characterization of CD4+ T-cell receptors cross-reactive for SARS-CoV-2 and endemic coronaviruses
Arbor G Dykema[SUP] 1 [/SUP], Boyang Zhang[SUP] 2 [/SUP], Bezawit A Woldemeskel[SUP] 3 [/SUP], Caroline C Garliss[SUP] 3 [/SUP], Laurene S Cheung[SUP] 4 [/SUP], Dilshad Choudhury[SUP] 1 [/SUP], Jiajia Zhang[SUP] 1 [/SUP], Luis Aparicio[SUP] 1 [/SUP], Sadhana Bom[SUP] 1 [/SUP], Rufiaat Rashid[SUP] 1 [/SUP], Justina X Caushi[SUP] 1 [/SUP], Emily Han-Chung Hsiue[SUP] 1 [/SUP], Katherine Cascino[SUP] 3 [/SUP], Elizabeth A Thompson[SUP] 5 [/SUP], Abena K Kwaa[SUP] 3 [/SUP], Dipika Singh[SUP] 1 [/SUP], Sampriti Thapa[SUP] 1 [/SUP], Alvaro A Ordonez[SUP] 6 [/SUP], Andrew Pekosz[SUP] 7 [/SUP], Franco R D'Alessio[SUP] 3 [/SUP], Jonathan D Powell[SUP] 1 [/SUP], Srinivasan Yegnasubramanian[SUP] 1 [/SUP], Shibin Zhou[SUP] 5 [/SUP], Drew M Pardoll[SUP] 1 [/SUP], Hongkai Ji[SUP] 2 [/SUP], Andrea L Cox[SUP] 5 [/SUP], Joel N Blankson[SUP] 3 [/SUP], Kellie N Smith[SUP] 4 [/SUP]
Affiliations
- PMID: 33830946
- DOI: 10.1172/JCI146922
Abstract
Background: Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to cross-recognition by T-cells specific for common cold coronaviruses (CCCs). True T-cell cross-reactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.
Methods: We used the ViraFEST platform to identify T cell responses cross-reactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC cross-reactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.
Results: Memory CD4+ T-cell clonotypes that cross-recognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Cross-reactive T-cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to mono-specific CD4+ T-cells, which was consistent with lower functional avidity of their TCRs for SARS CoV-2 relative to CCC.
Conclusions: For the first time, our data confirm the existence of unique memory CD4+ T cell clonotypes cross-recognizing SARS-CoV-2 and CCCs. The lower avidity of cross-reactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that pre-existing CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these cross-reactive T-cell responses impact clinical outcomes in COVID-19 patients.
Keywords: COVID-19; Immunology; Imprinting; MHC class 2; T cells.