Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals - 05/06/24

Doi : 10.1016/j.jaci.2023.12.011

Ottavia M. Delmonte, MD, PhD ^a,^⁎^{^{∗
These authors contributed equally to this work as co-first authors.}} , Cihan Oguz, PhD ^b,^{^{∗
These authors contributed equally to this work as co-first authors.}}, Kerry Dobbs, BS ^a,^{^{‡
These authors contributed equally to this work as co-second authors.}}, Katherine Myint-Hpu, PNP ^a,^{^{‡
These authors contributed equally to this work as co-second authors.}}, Boaz Palterer, MD, PhD ^a,^{^{‡
These authors contributed equally to this work as co-second authors.}}, Michael S. Abers, MD, MPH ^a, Deborah Draper, RN ^a, Meng Truong, RN ^a, Ian M. Kaplan, PhD ^c, Rachel M. Gittelman, PhD ^c, Yu Zhang, PhD ^a, Lindsey B. Rosen, PhD ^a, Andrew L. Snow, PhD ^a,^d, Clifton L. Dalgard, PhD ^e,^f, Peter D. Burbelo, PhD ^g, Luisa Imberti, MD ^h, Alessandra Sottini, PhD ^h, Eugenia Quiros-Roldan, MD ⁱ, Francesco Castelli, MD ⁱ, Camillo Rossi, MD, PhD ^j, Duilio Brugnoni, MD ^k, Andrea Biondi, MD ^l, Laura Rachele Bettini, MD ^l, Mariella D’Angio, MD ^l, Paolo Bonfanti, MD ^m, Megan V. Anderson, RN, BA ⁿ, Annalisa Saracino, MD ^o, Maria Chironna, MD ^p, Mariantonietta Di Stefano, PhD ^q, Jose Ramon Fiore, MD ^q, Teresa Santantonio, MD ^q, Riccardo Castagnoli, MD, PhD ^r,^s, Gian Luigi Marseglia, MD ^r,^s, Mary Magliocco, RN ^t, Marita Bosticardo, PhD ^a, Francesca Pala, PhD ^a, Elana Shaw, BS ^a, Helen Matthews, RN ^t, Sarah E. Weber, PhD ^t, Sandhya Xirasagar, PhD ^u, Jason Barnett, PhD ^u, Andrew J. Oler, PhD ^u, Dimana Dimitrova, MD ^v, Jenna R.E. Bergerson, MD ^a, David H. McDermott, MD ^w, V. Koneti Rao, MD ^a, Philip M. Murphy, MD, PhD ^w, Steven M. Holland, MD ^a, Andrea Lisco, MD, PhD ⁿ, Helen C. Su, MD, PhD ^a, Michail S. Lionakis, MD, ScD ^a, Jeffrey I. Cohen, MD ^x, Alexandra F. Freeman, MD, PhD ^a, Thomas M. Snyder, PhD ^c, Justin Lack, PhD ^b, Luigi D. Notarangelo, MD ^a,^⁎
^a Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^b Integrated Data Sciences Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^c Adaptive Biotechnologies, Seattle, Wash
^d Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Md
^e Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Md
^f The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, Md
^g Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md
^h Section of Microbiology, University of Brescia, ASST Spedali Civili, Brescia, Italy
ⁱ Department of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili, Brescia, Italy
^j Direzione Sanitaria, ASST Spedali Civili, Brescia, Italy
^k Laboratorio Analisi Chimico-Cliniche, ASST Spedali Civili, Brescia, Italy
^l Pediatric Department and Centro Tettamanti-European Reference Network on Paediatric Cancer, European Reference Network on Haematological Diseases, and European Reference Network on Hereditary Metabolic Disorders, University of Milano-Bicocca-Fondazione MBBM, Monza, Italy
^m Department of Infectious Diseases, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
ⁿ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^o Clinic of Infectious Diseases, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, University of Bari, Bari, Italy
^p Hygiene Section, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Bari, Italy
^q Department of Medical and Surgical Sciences, Section of Infectious Diseases, University of Foggia, Foggia, Italy
^r Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
^s Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
^t Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^u Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^v Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Md
^w Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^x Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md

^∗Corresponding author: Ottavia M. Delmonte, MD, PhD, or Luigi D. Notarangelo, MD, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 10, Rm 6-4750 (O.M.D.)/Rm 5-3750 (L.D.N.), 10 Center Dr—MSC, Bethesda, MD 20892.Laboratory of Clinical Immunology and MicrobiologyNational Institute of Allergy and Infectious DiseasesNational Institutes of HealthBldg 10Rm 6-4750 (O.M.D.)/Rm 5-3750 (L.D.N.)10 Center Dr—MSCBethesdaMD20892

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Abstract

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.

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

Abbreviations used : CDR3, COVID-19, GLIPH2, HCW, HTS, IEI, IFN-1, IQR, MIRA, N, ORF, RBD, S, SARS-CoV-2, TCR, TRB

Plan

Methods

Characteristics of patients and controls of the COVID-19 cohort

Characteristics of immunodeficient patients and health care workers of the SARS-CoV-2 vaccine cohort

Measurement of SARS-CoV-2–specific anti-S and anti-N antibodies and of anti–IFN-1 antibodies

HLA typing

TCR-β repertoire analysis

Statistical methods

Results

Characteristics of patients and controls in the COVID-19 cohort

Effects of age and disease severity on SARS-CoV-2–specific TCR repertoire

Epitope landscape of the SARS-CoV-2–specific clonotypes

HLA association and SARS-CoV-2–specific clonotypes in patients with COVID-19 with anti–IFN-1 antibodies

Breadth and epitope specificity of SARS-CoV-2 S protein–specific T-cell clonotypes in response to COVID-19 mRNA vaccines in HCWs and in patients with IEIs

Discussion

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Vol 153 - N° 6

P. 1655-1667 - juin 2024 Retour au numéro

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Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals - 05/06/24

Abstract

Background

Objective

Methods

Results

Conclusions

Plan

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