In a recent article published in the journal PLoS ONE, the researchers showed that the nucleocapsid (N) and spike (S) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) did not activate γδ T cells. and dendritic cells (DC).
Study: Spike and SARS-CoV-2 nucleocapsid proteins fail to activate human dendritic cells or γδ T cells. Image credit: Kateryna Kon / Shutterstock
Fund
The host immune response to SARS-CoV-2 significantly influences 2019 coronavirus disease outcomes (COVID-19). Severe SARS-CoV-2 is related to the activation and migration of neutrophils and macrophages into the lungs and increased serum levels of cytokines and chemokines such as interleukin-6 (IL-6), IL-1β, interferon-γ (IFN-γ) – caused protein 10 (IP-10; also called CXCL10) and tumor necrosis factor-α (TNF-α). It is also associated with functional depletion and depletion of circulating CD4 and CD8 T cells, B cells, natural killer (NK) cells, follicular helper T cells, and innate T cells such as mucosa-associated invariant T cells (MAIT), natural killer T cells. (NKT) cells and γδ T cells. Although γδ T cells may play a role in protection against SARS-CoV-2, the mechanism behind the process is unknown.
About the study
In the present work, the researchers examined the two most prevalent SARS-CoV-2 structural proteins, S and N, that provide immunogenic peptides for conventional T cell identification. This was to determine whether they could trigger subsets of human γδ T cells, such as Vδ2 and Vδ1 T cells, either directly or in the vicinity of dendritic (DC) cells. The team analyzed whether N or S proteins can stimulate cytokine generation by γδ T cells with or without DC.
Anticoagulated blood samples were taken with ethylenediaminetetraacetic acid (EDTA) from two patients with COVID-19 at St. John’s Hospital. James of Dublin and healthy volunteers from the Irish Blood Transfusion Service. It is important to note that SARS-CoV-2 N and S recombinant proteins were used for the experiments.
Results
The results of the study indicated that SARS-CoV-2 N, S proteins, or peptides that match the immunodominant areas of these proteins did not directly stimulate Vδ2 or Vδ1 T cells to generate TNF-α or IFN-γ, nor within peripheral blood mononuclear cells (PBMC). ) or in total γδ T cell cultures. In addition, S, N proteins, or peptide mixtures did not specifically induce DC maturation or cytokine generation. In addition, when co-cultured DCs were treated with S and N proteins or peptides, no stimulation of TNF-α or IFN-γ generation was observed.
Initially, the authors realized that the SARS-CoV-2 N protein elicited robust generation of IL-12 by DC and subsequent stimulation of Vδ2 and Vδ1 T cells. However, the digestion of the N protein protease did not stop this action. Exposure to a second N protein preparation had no stimulating effects on either γδ T cells or DCs. Therefore, the observed stimulatory function of N was probably associated with contaminated non-proteinaceous material, such as lipopolysaccharide (LPS).
Interestingly, DC LPS activation resulted in IL-12 production and subsequent activation of Vδ2 and Vδ1 T cells. This inference suggests that cytokine DC production contributes to γδ T cell stimulation and that DC excitation in response to ribonucleic acid (RNA) detection could similarly stimulate cells. T γδ. The release of TNF-α and IL-12 by DC after activation with polyinosinic: polycytylic acid and the subsequent generation of TNF-α and IFN-γ by cocultured T γδ T cells support this theory. Therefore, the signals generated by myeloid cell stimulation were probably the secondary cause of γδ T cell stimulation in patients with COVID-19.
The scientists found that protein S did not activate the generation of TNF-α or IL-12 by DC from monocyte stem. On the other hand, LPS, a different toll-like receptor 4 (TLR4) agonist, triggered DC to produce potent cytokines and successively stimulate γδ T cells. Because the SARS-CoV-2 S protein could not excite DC in the current configuration, it indicates that DC derived from monocytes and macrophages will react to TLR4 ligation differently or that various forms of LPS will activate DC and macrophages differently. .
Conclusions
Collectively, the results of the study indicate that SARS-CoV-2 S and N proteins do not stimulate DC or γδ T cells. The team suggests that immunological identification of other structural proteins SARS-CoV-2 or viral RNA by γδ T cells or other immune cells, including DCs, that release γδ T cell stimulating ligands or cytokines , is what causes γδ T cell activation in SARS. -Patients with CoV-2.
The authors emphasized the need for additional research using whole SARS-CoV-2 virions instead of recombinant S and N proteins. This was to determine whether SARS-CoV-2 can directly activate γδ T cells or whether it must first cause the generation of cytokines or γδ T cell-stimulating ligands by other innate immune cells, such as DC.