The SARS-CoV-2 T-cell immunity is directed against the spike, membrane, and nucleocapsid protein and associated with COVID 19 severity

Authors: C.J. Thieme et al.

Link to paper: https://www.medrxiv.org/content/10.1101/2020.05.13.20100636v1.full.pdf

Journal/ Pre-Print: medRxiv

Tags: Immunology/Immunity

Research Highlights

1. In COVID19 patients, T cells react to peptides from the SARS-CoV-2 Spike, Matrix and and Nucleocapsid proteins.

2. Higher percentage of CD4+ than CD8+ T cells are reactive to SARS-CoV-2 with both harboring different recognition-patterns.

Summary 

The authors assess the SARS-CoV-2 directed T cell responses in moderate, severe and critical COVID-19 patients. To this end, they used overlapping peptide pools from SARS-Cov2 Spike (S), Matrix (M) and Nucleocapsid (N) proteins to stimulate PBMCs from COVID-19 patients. They find a significant frequency of M and N-reactive T cell responses in parallel to the well-studied S protein. The study highlights the relevance of focusing not only on S, but also on M and N protein for intervention strategies. Critical COVID-19 patients have similar percentages of SARS-CoV-2 S-, M-, and N-protein reactive CD4 and CD8 T cells as those of mild COVID19 patients. CD4+ T cell reactive responses were greater in terms of percentage of patients and range of targets than CD8 T cell responses. However, reactive CD8 T cells harboured effector/memory phenotypes that suggest either a pre-existing immunity or an earlier CD8+ T cell activation.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19

Study Type

· In vitro study using patient samples

Strengths and limitations of the paper

Novelty: The authors looked at T cell responses against peptide pools not only from S but also M and N SARS-CoV-2 protein in moderate, severe and critical COVID19 patients in the same study.

Standing in the field: Recently other studies assessed the target landscape of T-cell responses to SARS-Cov2 infected patients:

- In moderate and healthy donors using “megapools” of peptides well designed: https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3

- In moderate to severe patients: https://www.medrxiv.org/content/10.1101/2020.04.11.20062349v1

Appropriate statistics:

- small sample size (28 in total)

- appropriate statistics in terms of statistical correction applied

Viral model used: Peptide pools obtained from Miltenyi

Translatability: Study emphasises importance of analysing adaptive immune responses (humoral and cellular) against M and N proteins as focussing only on the S protein may be too reductive.

Main limitations:

- Study design not clear, they used multiple samples per patients which they allocated to different stimulation conditions (not every patient seems allocated in the 3 conditions)

- Authors should show absolute numbers instead of percentages of reactive T cells in the comparison with disease severity, as lymphopenia is observed in critical COVID19 patients.

- Did not show the percentage of the positive cells in FACS gates for the gating strategy

- Peptide pools are not as complete as in other studies (https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3)

- It would have been informative to assess reactivity across the different stimulation conditions for each patient.

- Did not study differential responses during the progression of the disease (e.g. at time of hospitalisation and after recovery).