Landscape of T‐cell repertoires with public COVID‐19‐associated T‐cell receptors in pre‐pandemic risk cohorts

Abstract

Objectives T cells have an essential role in the antiviral defence. Public T‐cell receptor (TCR) clonotypes are expanded in a substantial proportion of COVID‐19 patients. We set out to exploit their potential use as read‐out for COVID‐19 T‐cell immune responses. Methods We searched for COVID‐19‐associated T‐cell clones with public TCRs, as defined by identical complementarity‐determining region 3 (CDR3) beta chain amino acid sequence that can be reproducibly detected in the blood of COVID‐19 patients. Of the different clonotype identification algorithms used in this study, deep sequencing of brain tissue of five patients with fatal COVID‐19 delivered 68 TCR clonotypes with superior representation across 140 immune repertoires of unrelated COVID‐19 patients. Results Mining of immune repertoires from subjects not previously exposed to the virus showed that these clonotypes can be found in almost 20% of pre‐pandemic immune repertoires of healthy subjects, with lower representation in repertoires from risk groups like individuals above the age of 60 years or patients with cancer. Conclusion Together, our data show that at least a proportion of the SARS‐CoV‐2 T‐cell response is mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID‐19 courses.

T cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibodies and disease severity

“…Given that the severity of COVID-19 increases with age (41) and that we have shown that depth and breadth of the T cell response measured by this assay increases with disease severity, it is possible that diagnostic sensitivity could be lower in younger individuals. However, an analysis of the representation of public SARS-CoV-2-specific TCRs has suggested that representation of these TCRs is higher among individuals < 60 years of age compared with those older than 60 years of age (42). Based on these divergent data, additional analyses are needed to assess the sensitivity of the assay in younger and asymptomatic individuals.…”

Machine Learning Approaches to TCR Repertoire Analysis

“…Further insights are also provided by using sequence information based ML methods. In Simnica et al (168), COVID-19 public TCRs are investigated. GLIPH2 (81), one of the dissimilarity-based methods we reviewed, was used to cluster TCRs and select COVID-19 related TCRs by Student's T-test (similar to Emerson et al (16) introduced as one of the hypothesis test based methods).…”

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

“…A number of publications have reported sequences of T cell receptors (TCRs) recognizing some immunodominant epitopes of SARS-CoV-2 (Shomuradova et al, 2020; Chaurasia et al, 2021; Minervina et al, 2021; Snyder et al, 2020). It was demonstrated that TCRs specific to some epitopes are public (Shomuradova et al, 2020; Simnica et al, 2021; Nguyen et al, 2021) and have a high degree of mutual similarity, which is sometimes accompanied by strong biases in variable (V) and joining (J) gene usage. According to the structural data, the latter can be explained by germline-based epitope recognition (Wu et al, 2022).…”