In a recent study posted to the bioRxiv* preprint server, researchers investigated the 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 the T cell responses to acute infections and vaccinations.
Study: Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection. Image Credit: Kateryna Kon/Shutterstock
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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 develops completely. Various studies exploring the human leukocyte antigen (HLA)-peptide binding and single-cell transcriptome and protein sequences have expanded the 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 the 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 hold the key to understanding the mechanisms of T cell responses.
About the study
In the present study, the researchers sequenced the T cell receptor repertoire from ribonucleic acid (RNA) extracted from whole blood samples of healthcare workers in London, United Kingdom. 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 seronegative for the virus.
The blood samples were collected in the acute and convalescent stages of the 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 were sequenced. The richness and Shannon diversity index were calculated for the repertoire from sequences from the PCR positive and negative samples by determining the number of distinct sequences. Individual T cell receptors whose abundance changed significantly in the first five weeks were identified.
For each sample, the combined abundance of all expanded T cell receptors was plotted as a function of time to estimate clonal expansion. The expanded sets were also examined for cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus enriched T cell receptors to determine the T cells receptors enriched specifically for SARS-CoV-2.
Results
The results reported a strong but short-lived expansion of a small number of T cell receptors during the infection, whose peak coincided with the first positive PCR test. The complementarity determining region 3 (CDR3) of the T cells was found to be enriched for SARS-CoV-2-specific fully annotated sequences. However, the authors believe that bystander activation of pre-existing memory cells cannot be ruled out. Furthermore, the T cell receptor expansion 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. Hypothesis one is based on the presence of SARS-CoV-2-specific T cell receptors on memory T cells that are cross-reactive 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 precursor frequency presence of T cell receptors among the naive repertoire. Experiments with lymphocytic choriomeningitis virus infections in vaccinated and unvaccinated mice revealed epitope-specific expansion of T cell receptors in the early stages of the infection.
A search for T cell receptors with identical CDR3 receptors among naive and effector repertoires revealed that high endogenous frequency T cells were present in the naive compartments and were responsible for the T cell responses during the early stages of infection.
Furthermore, the T cell receptors that arise during the early stages of the infection and those that expand during the later stages of the infection had different naive repertoire distribution frequencies, indicating the role of the naive T cell receptor repertoire in early infection responses.
Conclusions
To summarize, 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 the rapid T cell responses in the early stages of SARS-CoV-2 infections were associated with high-frequency naive T cell precursors.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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