[HTML][HTML] HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children

RA Porritt, L Paschold, MN Rivas… - The Journal of …, 2021 - Am Soc Clin Investig
RA Porritt, L Paschold, MN Rivas, MH Cheng, LM Yonker, H Chandnani, M Lopez…
The Journal of clinical investigation, 2021Am Soc Clin Investig
Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome
associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome,
which is triggered by bacterial superantigens. Superantigen specificity for different Vβ chains
results in Vβ skewing, whereby T cells with specific Vβ chains and diverse antigen specificity
are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR
repertoire of MIS-C patients and found a profound expansion of TCRβ variable gene 11-2 …
Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vβ chains results in Vβ skewing, whereby T cells with specific Vβ chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRβ variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vβ chain encoded by TRBV11-2 (Vβ21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.
The Journal of Clinical Investigation