Cross-Reactive and Mono-Reactive SARS-CoV-2 CD4+ T Cells in Prepandemic and COVID-19 Convalescent Individuals

Class II tetramer reagents were used to identify SARS-CoV-2-specific CD4+ T cell epitopes and study these epitope-specific T cells ex vivo. Dominant and subdominant epitopes were identified. Majority of epitopes identified have <67% amino acid sequence identity with endemic coronaviruses and are unlikely to elicit cross-reactive T cell responses. However, four Spike epitopes highly homologous with endemic coronaviruses were identified. Specific T cells for three such DR-restricted epitopes were present at relatively low frequencies in convalescent individuals. Spike cross-reactive memory T cells that recognized a DPB1*04:01 restricted epitope were detected in uninfected DPB1*04:01 persons at low frequencies, with higher frequencies and different phenotypes in convalescent persons. Patterns of T cell cross-reactivity between SARS-CoV-2 and endemic coronaviruses differed amongst DPB1*04:01 persons. Spike cross-reactive T cells expanded to a lesser extent compared to mono-reactive T cells in these individuals and only contributed a small proportion of the overall Spike-specific CD4+ T cells.Funding Information: Funding was provided from NIH grants 3U19AI135817-04S1 (WWK), 1R21AI163999 (DMK) and NIH contract HHSN75N93019C00063 (DMK).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The study was approved by Benaroya Research Institute and University of Washington Institutional Review Boards and all blood samples were obtained with informed consent from the participants.