Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals

• Published in: PLoS pathogens Vol. 17; no. 12; p. e1010203
• Main Authors: Johansson, Alexandra M., Malhotra, Uma, Kim, Yeseul G., Gomez, Rebecca, Krist, Maxwell P., Wald, Anna, Koelle, David M., Kwok, William W.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2021; Public Library of Science (PLoS)
• Subjects: Alleles; Amino acid sequence; Amino acids; Antigenic determinants; Avidity; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell lines; Convalescence; Coronaviruses; COVID-19; COVID-19 - epidemiology; COVID-19 - immunology; Cross Reactions; Cross-reactivity; Epidemiology; Epitopes; Epitopes, T-Lymphocyte - immunology; Experiments; Frequency analysis; Histocompatibility antigen HLA; Humans; Identification and classification; Influenza; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Nucleocapsids; Pandemics; Peptides; Peripheral blood mononuclear cells; Population genetics; Proteins; Reagents; Research and Analysis Methods; SARS-CoV-2 - immunology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - immunology; T cell receptors; T cells; Viral diseases; Viruses; World population; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010203

Class II tetramer reagents for eleven common DR alleles and a DP allele prevalent in the world population were used to identify SARS-CoV-2 CD4+ T cell epitopes. A total of 112, 28 and 42 epitopes specific for Spike, Membrane and Nucleocapsid, respectively, with defined HLA-restriction were identified. Direct ex vivo staining of PBMC with tetramer reagents was used to define immunodominant and subdominant T cell epitopes and estimate the frequencies of these T cells in SARS-CoV-2 exposed and naïve individuals. Majority of SARS-CoV-2 epitopes identified have <67% amino acid sequence identity with endemic coronaviruses and are unlikely to elicit high avidity cross-reactive T cell responses. Four SARS-CoV-2 Spike reactive epitopes, including a DPB1*04:01 restricted epitope, with ≥67% amino acid sequence identity to endemic coronavirus were identified. SARS-CoV-2 T cell lines for three of these epitopes elicited cross-reactive T cell responses to endemic cold viruses. An endemic coronavirus Spike T cell line showed cross-reactivity to the fourth SARS-CoV-2 epitope. Three of the Spike cross-reactive epitopes were subdominant epitopes, while the DPB1*04:01 restricted epitope was a dominant epitope. Frequency analyses showed Spike cross-reactive T cells as detected by tetramers were present at relatively low frequency in unexposed people and only contributed a small proportion of the overall Spike-specific CD4+ T cells in COVID-19 convalescent individuals. In total, these results suggested a very limited number of SARS-CoV-2 T cells as detected by tetramers are capable of recognizing ccCoV with relative high avidity and vice versa. The potentially supportive role of these high avidity cross-reactive T cells in protective immunity against SARS-CoV-2 needs further studies.