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

Abstract

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.

SARS-CoV-2 epitope–specific CD4 + memory T cell responses across COVID-19 disease severity and antibody durability

“…It should be noted, however, that these epitopes do not have significant sequence homology with common cold coronaviruses, which may account for the lack of significant pre-existing T cell immunity detected in unexposed subjects, as has been documented with larger-scale screens of SARS-CoV-2 CD4 + T cell epitopes using different methods ( 17 , 21 , 34 – 36 ). Tetramers may also be less likely to pick up lower affinity cells with a higher degree of cross-reactivity across coronavirus strains detected by AIM assays ( 37 ). This could also influence the phenotypic differences we observed between mild and severe disease, given previous findings suggesting lower affinity cells comprise a larger proportion of the SARS-CoV-2-specific CD4 + T cell response in severe disease ( 38 ).…”

High and Sustained Ex Vivo Frequency but Altered Phenotype of SARS-CoV-2-Specific CD4+ T-Cells in an Anti-CD20-Treated Patient with Prolonged COVID-19

“…While SARS-CoV-2-specific CD8 + T-cells have already been phenotypically studied in this context [26][27][28][29], SARS-CoV-2-specific CD4 + T-cells have rarely been studied through major histocompatibility complex (MHC) multimer staining [30][31][32]. In particular, we lack data on the longitudinal ex vivo frequency and phenotype over the course of the disease.…”

Development of a T Cell-Based COVID-19 Vaccine Using a Live Attenuated Influenza Vaccine Viral Vector

“…This candidate, FluCoVac-28, had a high ability to grow in both eggs and MDCK cells, induced robust influenza-specific humoral and cellular responses and was able to activate memory T cells in PBMCs of COVID-19 recovered patients. Moreover, the inserted T-cassette contained rather extended fragments of coronavirus proteins enriched with T-cell epitopes of various HLA restriction, including such immunogenic epitopes as RLQSLQTYV [58,71,72], RLDKVEAEV [72,73], GMEVTPSGTWLTYTGAIKLD [36,74], and others. This selected prototype was further studied in Golden Syrian hamsters.…”