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Children with coronavirus disease 2019 (COVID-19) sometimes develop multisystem inflammatory syndrome in children (MIS-C), which is associated with high morbidity. The underlying mechanism associated with T cells is described by the researchers in a new study published on the prepress server bioRxiv* in November 2020, in response to superantigen activation.
Common superantigen-induced T cell activation?
Toxic shock syndrome (TSS) and MIS-C share many similarities, with extensive, unregulated inflammation being characteristic of both. This study looked at the presence of hyperinflammation in multiple body systems in children with COVID-19. These children have experienced abdominal pain, diarrhea and rashes or have had a weakening of the heart, sometimes leading to cardiogenic shock. Oddly, these were not associated with severe respiratory symptoms. This suggests that MIS-C is due to an extrapulmonary infection of SARS-CoV-2 or a post-infectious inflammatory response.
TSS is also similar and is the result of superantigen stimulation, such as staphylococcal enterotoxin B (SEB). Superantigens are bacterial molecules that are very potent in binding T cell receptors (TCRs) and class II MHC molecules.
TCR V-beta tilt
The first bond engages specific beta chains of TCRs, involving their variable domains without having to rely on the complementary determinant region 3 (CDR3). This allows them to directly and nonspecifically activate T lymphocytes and induce their proliferation, as well as eliciting the cytokine-driven unregulated hyperinflammatory response (called cytokine storm).
Specific superantigens bind to different TCR V-beta chains, and therefore T cells with these specific V-beta chains that bind to a wide range of antigens will be overexpressed in these patients.
Complex formation between SARS-CoV-2 peak, TCR containing Vβ11-2 and MHCII and comparative analysis of Vβ TCR sequences homologous to Vβ11-2. (A) Binding of TCR (with Vβ chain sequentially identical to that of the TRBV11-2 gene product) to the SAg-like region of the SARS-CoV-2 peak. TCR α and β chains are shown in magenta and cyan, respectively. The β chain tightly binds the SAg-like region (E661 to R685; colored yellow). The spike subunits are colored dark red, beige, and gray; and the neurotoxin motif (299-356), green. (BC) Ternary complex between spikes, the same TCR and MHCII (green and close-up view of the interfacial interactions between two basic residues, R682 and R683, on the SAg-like region of the spike and the acid residues (D67 and D68) of TCR Vβ (D67 and D68) and TCRα.
Superantigen point pattern
The current study is based on the presence of a superantigen-like motif in the SARS-CoV-2 spike antigen. This binds to high affinity TCRs and class II MHC, forming a three-way complex. This motif closely resembles a staphylococcal superantigen in terms of sequence and structure. The slope of V-beta TCR observed in adults with severe hyperinflammatory COVID-19 phenotypes is similar to the type of immune response seen in superantigen-induced responses.
Variable gene expansion beta TCR
Researchers explored the range of expression of TCR in MIS-C with reference to V-beta inclination and signs of superantigen activation. They found that the TCR 11-2 beta variable gene (TRBV11-2) was significantly expanded. In mild MIS-C, there was a wider range of TCR, just like in mild adult COVID-19, compared to severe MIS-C or COVID-19.
MIS-C patients showed TRBV gene expansion compared to patients with fever but without SARS-CoV-2 infection. In severe disease, specific TRBV genes were exclusively overrepresented, i.e., TRBV11-2, TRBV24-1, and TRBV11-3 compared to controls with fever only or patients with mild MIS-C.
The latter showed an expansion of the TRBV-28 alone. Again, the use of TRBV11-2 was correlated with the expression of inflammatory cytokines such as TNF-α, IFN-γ, IL-6 and IL-10 and with severe pediatric disease. This model was found to be valid regardless of age in the severe MIS-C group.
Furthermore, TRBV11-2 expansion was related to PCR positivity rather than positive serological results. Over half of patients with this pattern were PCR positive, compared with zero patients without TRBV11-2 expansion. These data indicate an “association of TRBV11-2 expansion with active SARS-CoV-2 infection”.
Junctional diversity with TRBV11-2 expansion
Since CDR3 is not involved in superantigen interactions, the researchers expected a high degree of junctional diversity at the V (D) J junction in TCR with the use of TRBV11-2 in severe MIS-C. This was confirmed by the discovery that CDR3 / J genes in this subset of patients showed zero overlap, indicating high diversity. This also agrees with the canonical expansion profile observed with superantigen-induced activation.
TRAV8-4 was the most expanded gene among TRAVs in patients with severe MIS-C, but no inclination of TRAV was observed among patients with mild MIS-C.
TRBV24-1 was overrepresented in adult patients with severe COVID-19, but less so in severe MIS-C patients. The single patient who had robust expansion of the latter was a 15-year-old.
Cytokine storm
TRBV11-2 expansion was related to MIS-C severity. Furthermore, the serum levels of cytokines in these patients agreed with those found in patients with responses activated by hyperimmune superantigens.
Severe MIS-C is associated with a cytokine storm, which can cause the formation of autoimmune antibodies against endothelial, immune, and myocardial cells, among others, indicating a loss of tolerance of auto antigen B cells. The superantigens also affect T-cell B cell antigens through their binding to MHC class II B cells, promoting their differentiation into immunoglobulin-secreting cells and the activation of polyclonal and monoclonal B lymphocytes.
TRBV11-2 binds to the spike antigen
Researchers also conducted modeling studies indicating CDR3-independent engagement of TRBV11-2 with a polybasic P681RRAR insert, within the superantigen-like motif found on the SARS-CoV-2 spike protein.
Implications
The study concludes: “These data suggest that the SARS-CoV-2 spike may act as a superantigen to trigger the development of MIS-C and cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches. . “This could include anti-SEB antibodies – found in most people over 12, but lower in those over 70 – or drugs that prevent superantigen engagement by mimicking the peptide.
Further exploration will reveal the phenotypic and functional characterization of T cells using TRBV11-2 in these patients, shedding light on the mechanisms underlying disease manifestations.
*Important Notice
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or treated as consolidated information.
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