Clonal diversity predicts persistence of SARS-CoV-2 epitope-specific T-cell response

Abstract

T cells play a pivotal role in reducing disease severity during SARS-CoV-2 infection and formation of long-term immune memory. We studied 50 COVID-19 convalescent patients and found that T cell response was induced more frequently and persisted longer than circulating antibodies. We identified 756 clonotypes specific to nine CD8+ T cell epitopes. Some epitopes were recognized by highly similar public clonotypes. Receptors for other epitopes were extremely diverse, suggesting alternative modes of recognition. We tracked persistence of epitope-specific response and individual clonotypes for a median of eight months after infection. The number of recognized epitopes per patient and quantity of epitope-specific clonotypes decreased over time, but the studied epitopes were characterized by uneven decline in the number of specific T cells. Epitopes with more clonally diverse TCR repertoires induced more pronounced and durable responses. In contrast, the abundance of specific clonotypes in peripheral circulation had no influence on their persistence.

Architecture of the SARS-CoV-2-specific T cell repertoire

“…One particularly important factor is the time of sampling: at the peak of infection, more than 10% of total CD8 + T cells may be specific to a single SARS-CoV-2 epitope ( 21 , 26 ). A month after infection, the frequency of most epitope-specific T cell populations is typically < 1% of total CD8 + T cells ( 24 , 32 – 35 ).…”

“…In general, peripheral selection and expansion of antigen-specific clonotypes driven by persistent pathogens leads to a higher proportion of shared clones among abundant clonotypes ( 50 ). The overlap of the overall non-antigen specific TCR repertoire between individuals is significantly higher in COVID-19 patients than in healthy individuals ( 41 ), and this is primarily because some epitopes of SARS-CoV-2 tend to give rise to shared, public clonotypes ( 35 , 36 , 51 ). Public clonotypes tend to have short CDR3 regions and arise from specific V(D)J-rearrangement events that occur with higher probability ( 28 ).…”

“…During SARS-CoV-2 infection, the diversity and clonality of the antigen-specific TCR repertoire peaks within 8–14 days, then contracts slightly ( 25 , 59 ) before returning to basal levels within one week after virus elimination ( 60 ). A SARS-CoV-2 specific TCR repertoire can be detected in the vast majority of convalescent patients, persisting for up to 15 months after viral clearance with a slight decrease ( 35 , 42 , 59 ) or even increase of clonal diversity ( 61 ). Moreover, SARS-CoV-2 epitope-specific T cells are able to proliferate in individuals who were vaccinated after infection ( 42 ) or in the re-detectable positive cases (Y.…”

“…The durability of an antigen-specific response is determined by characteristics such as the publicity, diversity, and clonality of clonotypes recognizing that antigen ( 35 , 51 ). It has been shown that long-term immunity is principally mediated by the clonal diversity of the antigen-specific T cell response ( 35 , 61 ), whereas clonality does not appear to play a significant role ( 35 ). In some cases, however, dominant clones in the acute phase coincide with those found in the recovery phase ( 59 ).…”

“…Despite numerous attempts to predict the longevity of virus-specific T cell immune response based on repertoire characteristics ( 35 , 51 , 68 , 69 ), Bensouda Koraichi et al. study surmised that TCR clonotypes dynamic can be described by geometric Brownian motion.…”