Temporal TCR dynamics and epitope diversity mark recovery in severe COVID-19 patients
Kriti Khare, Sunita Yadav, Sayanti Halder, Yogiraj Ray, Dipyaman Ganguly, Rajesh Pandey
Frontiers in Immunology, doi:10.3389/fimmu.2025.1582949
Introduction: Severe COVID-19 is characterized by immune dysregulation, with T cells playing a central role in disease progression and recovery. However, the longitudinal dynamics of the T cell receptor (TCR) repertoire during the course of severe illness remain unclear. Methods: To investigate temporal changes in adaptive immunity, we analyzed peripheral blood samples from the ICU-admitted severe COVID-19 patients (n = 36) collected at three time points: Day 1 (T1), Day 4 (T2), and Day 7 (T3). Bulk RNAsequencing was performed to extract TCR repertoires, and cytokine profiles were assessed in parallel. TCR clonotypes were annotated using VDJdb and TCRex to infer potential epitope specificities. Results: By T3, we observed a 2.3-fold expansion in TCR clonotypes along with increased TCR-b (TRB) chain usage, indicating the emergence of a broad polyclonal T cell response. In contrast, TCR-g (TRG) chain prevalence declined. Pro-inflammatory cytokines, including IL-1b and IL-6, were reduced over time, marking a shift toward immune resolution. Changes in CDR3 motifs and preferential TRBV gene segment usage were detected, suggesting repertoire adaptation. Additionally, annotated TCR clonotypes at T3 mapped to SARS-CoV-2 and other pathogen-associated epitopes (e.g., CMV, Plasmodium), reflecting possible cross-reactivity or memory T cell recruitment. Discussion: These findings suggest a coordinated transition from immune dysfunction to recovery in severe COVID-19, marked by expanding TCR diversity, reduced inflammation, and predicted broadening of antigen recognition. The integrated analysis of TCR repertoire dynamics and cytokine profiles provides insights into the adaptive immune mechanisms underlying viral clearance and immune stabilization.
Ethics statement The studies involving humans were approved by Institutional Review Boards of CSIR-Indian Institute of Chemical Biology, Kolkata. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
Author contributions
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1582949/ full#supplementary-material
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"abstract": "<jats:sec><jats:title>Introduction</jats:title><jats:p>Severe COVID-19 is characterized by immune dysregulation, with T cells playing a central role in disease progression and recovery. However, the longitudinal dynamics of the T cell receptor (TCR) repertoire during the course of severe illness remain unclear.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To investigate temporal changes in adaptive immunity, we analyzed peripheral blood samples from the ICU-admitted severe COVID-19 patients (n = 36) collected at three time points: Day 1 (T1), Day 4 (T2), and Day 7 (T3). Bulk RNA-sequencing was performed to extract TCR repertoires, and cytokine profiles were assessed in parallel. TCR clonotypes were annotated using VDJdb and TCRex to infer potential epitope specificities.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>By T3, we observed a 2.3-fold expansion in TCR clonotypes along with increased TCR-β (TRB) chain usage, indicating the emergence of a broad polyclonal T cell response. In contrast, TCR-γ (TRG) chain prevalence declined. Pro-inflammatory cytokines, including IL-1β and IL-6, were reduced over time, marking a shift toward immune resolution. Changes in CDR3 motifs and preferential TRBV gene segment usage were detected, suggesting repertoire adaptation. Additionally, annotated TCR clonotypes at T3 mapped to SARS-CoV-2 and other pathogen-associated epitopes (e.g., CMV, Plasmodium), reflecting possible cross-reactivity or memory T cell recruitment.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>These findings suggest a coordinated transition from immune dysfunction to recovery in severe COVID-19, marked by expanding TCR diversity, reduced inflammation, and predicted broadening of antigen recognition. The integrated analysis of TCR repertoire dynamics and cytokine profiles provides insights into the adaptive immune mechanisms underlying viral clearance and immune stabilization.</jats:p></jats:sec>",
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