Tracking antigen‐specific TCR clonotypes in SARS‐CoV‐2 infection reveals distinct severity trajectories

Abstract

AbstractDespite the importance of antigen‐specific T cells in infectious disease, characterizing and tracking clonally amplified T cells during the progression of a patient's symptoms remain unclear. Here, we performed a longitudinal, in‐depth single‐cell multiomics analysis of samples from asymptomatic, mild, usual severe, and delayed severe patients of SARS‐CoV‐2 infection. Our in‐depth analysis revealed that hyperactive or improper T‐cell responses were more aggressive in delayed severe patients. Interestingly, tracking of antigen‐specific T‐cell receptor (TCR) clonotypes along the developmental trajectory indicated an attenuation in functional T cells upon severity. In addition, increased glycolysis and interleukin‐6 signaling in the cytotoxic T cells were markedly distinct in delayed severe patients compared to usual severe patients, particularly in the middle and late stages of infection. Tracking B‐cell receptor clonotypes also revealed distinct transitions and somatic hypermutations within B cells across different levels of disease severity. Our results suggest that single‐cell TCR clonotype tracking can distinguish the severity of patients through immunological hallmarks, leading to a better understanding of the severity differences in and improving the management of infectious diseases by analyzing the dynamics of immune responses over time.