Study suggests rapid expansion of naïve T cells can provide rapid and effective immune response to SARS-CoV-2 and other viral infections

In a recent study published on bioRxiv* preprint server, researchers investigated early T cell responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to understand the mechanisms of rapid clonal expansion that characterize T cell responses to infections acute and vaccinations.

Study: Large pre-existing T-cell clones induce early immunity against SARS-COV-2 and LCMV infection. Image Credit: Kateryna Kon/Shutterstock

Background

Strong and rapid T-cell responses in the early stages of infection are thought to play a role in limiting microbial growth or viral replication before humoral immunity fully develops. Various studies exploring peptide-human leukocyte antigen (HLA) binding and transcriptome and single-cell protein sequences have expanded knowledge about T cell epitopes and function.

Early T cell responses are associated with better clinical outcomes during SARS-CoV-2 infections, encouraging the development of vaccines based on T cell responses. However, immune responses have been difficult to study in early stages of an infection, which are further confounded by existing immunity from previous infections. The dynamics of T cell receptor repertoire development during early infections are thought to be key to understanding the mechanisms of T cell responses.

About the study

In the present study, researchers sequenced the repertoire of T-cell receptors from ribonucleic acid (RNA) extracted from whole blood samples from healthcare workers in London, UK. The study group included 41 healthcare workers who had positive polymerase chain reaction (PCR) tests for SARS-CoV-2 infection and six healthcare workers who were HIV-negative for the virus.

Blood samples were collected at the acute and convalescent stages of infection, which corresponded to 0-4 weeks and 12-14 weeks respectively. A total of 14.6 million T cell receptor alpha and beta genes have been sequenced. Shannon richness and diversity index were calculated for the repertoire from the sequences of PCR positive and negative samples by determining the number of distinct sequences. Individual T-cell receptors whose abundance changed significantly over the first five weeks were identified.

For each sample, the combined abundance of all expanded T cell receptors was plotted against time to estimate clonal expansion. The expanded sets were also screened for cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus enriched T cell receptors to determine enriched T cell receptors specifically for SARS-CoV-2 .

Results

The results reported a strong but short-lived expansion of a small number of T-cell receptors during infection, the peak of which coincided with the first positive PCR test. The complementarity determining region 3 (CDR3) of T cells was found to be enriched for fully annotated sequences specific to SARS-CoV-2. However, the authors believe that proximity activation of pre-existing memory cells cannot be ruled out. Additionally, expansion of the T-cell receptor was not observed in the PCR-negative control group.

The researchers developed two hypotheses to explain the high frequency of SARS-CoV-2-specific T cell precursors in the pre-pandemic T cell repertoire. The first hypothesis is based on the presence of SARS-CoV-2-specific T cell receptors on memory T cells that cross-react and recognize homologous epitopes from other circulating human coronaviruses.

The second hypothesis explored the possibility of the early and rapid expansion of SARS-CoV-2-specific T cell receptors associated with the high frequency presence of T cell receptor precursors among the naïve repertoire. Experiments with lymphocytic choriomeningitis virus infections in vaccinated and unvaccinated mice revealed specific epitope expansion of T-cell receptors in the early stages of infection.

A search for T cell receptors with identical CDR3 receptors among the naïve and effector repertoires revealed that high frequency endogenous T cells were present in the naïve compartments and were responsible for T cell responses during the early stages of the infection.

Moreover, T cell receptors that arise during the early stages of infection and those that develop during later stages of infection had different frequencies of distribution of the naïve repertoire, indicating the role of the T cell receptor repertoire. naïve T cells in early responses to infection.

conclusion

In summary, the study explored the dynamics of T-cell receptor changes to understand the mechanisms underlying rapid T-cell responses during the early stages of SARS-CoV-2 infections. The results indicated a rapid expansion of SARS-CoV-2-specific T cell receptors during early infection, coinciding with the first positive PCR test.

Additionally, experiments with lymphocytic choriomeningitis virus revealed that rapid T-cell responses in the early stages of SARS-CoV-2 infections were associated with high-frequency naïve T-cell precursors.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

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