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Review 1: "Landscape of Public T Cell Receptors Associated with Recovery from COVID-19"

Reviewer: Houda Alachkar (University of Southern California) 📗📗📗📗◻️

Published onApr 14, 2022
Review 1: "Landscape of Public T Cell Receptors Associated with Recovery from COVID-19"

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



The adaptive immune system plays a crucial role in protecting against viral infections. Thus, with the ongoing COVID-19 pandemic, there have been tremendous research efforts placed on the characterization and identification of SARS-CoV-2-specific T cells and establishing their potential protective role in COVID-19 patients 1–3. Simnica and colleagues have taken a unique approach of analyzing the clonal trajectories of TCR repertoires in patients recovering from COVID-19 to identify recovery-associated expanding TCR clones. Expanded TCR sequences were then mined in several cohorts of TCR repertoire that include both COVID-19 patients, pre-pandemic healthy controls, and patients with both solid and hematological malignancies. They identified several public TCR clones that were also shared by COVID-19 non-exposed individuals. The study also suggests that the low prevalence of these public TCR clones in individuals aged over 60 years and in patients with cancer (hematological and solid) may contribute to the high risk of COVID-19 infection and serious COVID-19 outcomes in these individuals.

The work is timely and needed as it confirms the presence of COVID-19 associated TCR clones and their role in protecting against SARS-CoV-2. It also builds on prior observations by previous studies demonstrating the presence of SARS-CoV-2-reactive T cells in ∼40–60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating “common cold” coronaviruses and SARS-CoV-2 1. The approach is also innovative, applying longitudinal tracking of TCR repertoire through the course of recovery from COVID-19. The study also reports patterns of cytokine profiles such as IL-6 and IL-10 for recovered versus fatal cases with COVID-19 that are consistent with prior studies 4,5. The observations related to the levels of IL-2 and IL-12 in COVID-19 patients are conflicting in prior studies 4,6–8, Simnica and colleagues reported higher levels of these two cytokines in recovered cases. The study has the potential of advancing knowledge and understanding in investigating the relationship between TCR repertoires as the immunological determinant of COVID-19 clinical outcomes.

The major weakness of the study is the small number of patients analyzed to identify recovery-associated expanded TCR clones. While the identified expanded clones were then mined in a larger cohort of COVID-19 patients, the initial list of expanded TCR clonotypes was generated from the repertoires of only two patients and with very different time courses for their TCR analysis (pat. 7 trajectory was previously reported 9 ). Considering the large heterogeneity and complexity of the TCR repertoire data and the sensitivity of these analyses to large number of variables such as ethnicity, age, pre or post-chemotherapy (for patients with cancer), a larger sample size to generate the recovery-associated expanded TCR clones would enhance the robustness of the analysis. In addition, since some of the identified 13 public TCR repertoires were also found in the COVID-19 fatal cases, it seems that it is the expansion of these clones during the disease course that correlates with their clinical outcome, rather than their presence in an individual. Thus, it would be relevant to address whether the difference observed between the risk groups and COVID-19 recovered patients or younger healthy individuals in the mean number of COVID-19 associated clones per repertoire is specific to COVID-19 associated TCR or a more general phenomenon that involves other public clones that are not COVID-19 specific. Furthermore, the basic characteristics of the TCR repertoires in these patients would be helpful such as measures of TCR diversity and clonal expansion, and how they differ among the different study populations.

In this manuscript, the authors cited the relevant and reliable literature to support the study background and their rationale. Limitations and future directions were discussed. The statistical analysis used seems to be appropriate. The authors shared the data with the proper repositories. It would add to the transparency of the data if the authors would also share the codes used in their computational analyses. Ethical concerns were well discussed by providing the IRB approvals, ethics committee approvals, and written informed consent. The format is well structured especially with the in brief/eTOC blurb, highlights, and summary sections. The messages in this work are well defined and well written in a logical manner.

Overall, the main claims in this manuscript are reliable and informative with room for improvement.


1. Grifoni, A. et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489–1501.e15 (2020).

2. Ni, L. et al. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity 52, 971–977.e3 (2020).

3. Le Bert, N. et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584, 457–462 (2020).

4. Han, H. et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microbes Infect. 9, 1123–1130 (2020).

5. Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020).

6. Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).

7. Osman, M. et al. Impaired natural killer cell counts and cytolytic activity in patients with severe COVID-19. Blood Adv 4, 5035–5039 (2020).

8. Zhang, B. et al. Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19. Front Mol Biosci 7, 157 (2020).

9. Schultheiß, C. et al. Next-Generation Sequencing of T and B Cell Receptor Repertoires from COVID-19 Patients Showed Signatures Associated with Severity of Disease. Immunity vol. 53 442–455.e4 (2020).

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