Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals

Ottavia M. Delmonte*, Cihan Oguz, Kerry Dobbs, Katherine Myint-Hpu, Boaz Palterer, Michael S. Abers, Deborah Draper, Meng Truong, Ian M. Kaplan, Rachel M. Gittelman, Yu Zhang, Lindsey B. Rosen, Andrew L. Snow, Clifton L. Dalgard, Peter D. Burbelo, Luisa Imberti, Alessandra Sottini, Eugenia Quiros-Roldan, Francesco Castelli, Camillo RossiDuilio Brugnoni, Andrea Biondi, Laura Rachele Bettini, Mariella D'Angio, Paolo Bonfanti, Megan V. Anderson, Annalisa Saracino, Maria Chironna, Mariantonietta Di Stefano, Jose Ramon Fiore, Teresa Santantonio, Riccardo Castagnoli, Gian Luigi Marseglia, Mary Magliocco, Marita Bosticardo, Francesca Pala, Elana Shaw, Helen Matthews, Sarah E. Weber, Sandhya Xirasagar, Jason Barnett, Andrew J. Oler, Dimana Dimitrova, Jenna R.E. Bergerson, David H. McDermott, V. Koneti Rao, Philip M. Murphy, Steven M. Holland, Andrea Lisco, Helen C. Su, Michail S. Lionakis, Jeffrey I. Cohen, Alexandra F. Freeman, Thomas M. Snyder, Justin Lack, Luigi D. Notarangelo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. Objective: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. Methods: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor β repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I– and class II–restricted SARS-CoV-2–specific responses and also identified several HLA allele–clonotype motif associations in patients with COVID-19, including a subcohort of anti–type 1 interferon (IFN-1)-positive patients. Results: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2–specific clonotypes targeted a broad range of HLA class I– and class II–restricted epitopes across the viral proteome. The presence of anti–IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2–specific clonotypes in patients with IEIs, including those who had failed to seroconvert. Conclusions: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti–IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
StateAccepted/In press - 2024
Externally publishedYes


  • anti–type 1 interferon antibodies
  • COVID-19
  • COVID-19 mRNA vaccine
  • inborn errors of immunity
  • SARS-CoV-2
  • T-cell receptor repertoire


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