Thomas M Snyder ¹ Rachel M Gittelman ¹ Mark Klinger ¹ Damon H May ¹ Edward J Osborne ¹ Ruth Taniguchi ¹ H Jabran Zahid ² Ian M Kaplan ¹ Jennifer N Dines ¹ Matthew T Noakes ¹ Ravi Pandya ² Xiaoyu Chen ¹ Summer Elasady ¹ Emily Svejnoha ¹ Peter Ebert ¹ Mitchell W Pesesky ¹ Patricia De Almeida ¹ Hope O'donnell ¹ Quinn Degottardi ¹ Gladys Keitany ¹ Jennifer Lu ¹ Allen Vong ¹ Rebecca Elyanow ¹ Paul Fields ¹ Julia Greissl ² Lance Baldo ¹ Simona Semprini ³ Claudio Cerchione ⁴ Fabio Nicolini ⁵ Massimiliano Mazza ⁵ Ottavia Maria Delmonte ⁶ Kerry Dobbs ⁶ Rocio Laguna-Goya ⁷ Gonzalo Carreño-Tarragona ⁸ Santiago Barrio ⁸ Luisa Imberti ⁹ Alessandra Sottini ⁹ Eugenia Quiros-Roldan ⁹ Camillo Rossi ⁹ Andrea Biondi ¹⁰ Laura Rachele Bettini ¹⁰ Mariella D'angio ¹⁰ Paolo Bonfanti ¹¹ Miranda F Tompkins ¹² Camille Alba ¹² Clifton Lee Dalgard ¹³ Vittorio Sambri ³ Giovanni Martinelli ⁴ Jason D. Goldman ^14,15 James Heath ¹⁶ Helen C. Su ⁶ Luigi Daniele Notarangelo ⁶ Estela Paz Artal ⁷ Joaquin Martinez-Lopez ⁸ Bryan Howie ¹ Jonathan M Carlson ² Harlan S Robins ^1*

• ¹ Adaptive Biotechnologies, Seattle, WA, United States
• ² Microsoft Research, Redmond, WA, United States
• ³ Unit of Microbiology - The Great Romagna Hub Laboratory, Pievesestina ITALY and DIMES, University of Bologna, Bologna, Emilia-Romagna, Italy
• ⁴ IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, FC, Italy
• ⁵ Immunotherapy, Cell Therapy and Biobank (ITCB), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, FC, Italy
• ⁶ Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
• ⁷ Department of Immunology, Hospital 12 de Octubre, i+12, CNIO, Complutense University, Madrid, Spain
• ⁸ Hematology Department, Hospital 12 de Octubre, i+12, CNIO, Complutense University, Madrid, Spain
• ⁹ Laboratorio CREA, Department of Infectious and Tropical Diseases, and Medical Officer, ASST Spedali Civili di Brescia and University of Brescia, Brescia, Italy
• ¹⁰ Department of Pediatrics and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale San Gerardo, Monza, Italy
• ¹¹ Department of Infectious Diseases, University of Milano-Bicocca-Ospedale San Gerardo, Monza, Italy
• ¹² The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
• ¹³ Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
• ¹⁴ Swedish Medical Center, Seattle, WA, United States
• ¹⁵ Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, United States
• ¹⁶ Institute for Systems Biology, Seattle, WA, United States

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides. Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared “public” T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3–7 = 85.1% [95% CI = 79.9–89.7]; Day 8–14 = 94.8% [90.7–98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1–98.3]). The approaches described in this work provide detailed insights into the adaptive immune response to SARS-CoV-2 infection, and they have potential applications in clinical diagnostics, vaccine development, and monitoring.