Distorted TCR repertoires define multisystem inflammatory syndrome in children

Area of Science:

• Immunology
• Virology
• Pediatrics

Background:

• Most children infected with SARS-CoV-2 have mild symptoms, but some develop severe multisystem inflammatory syndrome (MIS-C).
• The underlying immunological mechanisms driving MIS-C severity remain unclear.
• Understanding T cell receptor (TCR) repertoire alterations may elucidate MIS-C pathogenesis.

Purpose of the Study:

• To investigate TCR repertoire differences in children with MIS-C compared to those with mild COVID-19.
• To identify specific T cell populations or TCR features associated with MIS-C.

Main Methods:

• TCR sequencing was performed on samples from children with MIS-C (n=12) and mild COVID-19 (n=8).
• TCR repertoires were compared to pre-pandemic controls (n=8) and a large SARS-CoV-2-specific TCR dataset (Adaptive Biotechnologies MIRA).

Main Results:

• Children with MIS-C exhibited an expansion of TRBV11-2 T cell receptor chains with high junctional and CDR3 diversity.
• The CDR3 sequences of expanded TRBV11-2 clones in MIS-C patients deviated from known SARS-CoV-2 specific T cell clones.
• This deviation indicates a distortion of the overall TCR repertoire in MIS-C.

Conclusions:

• The findings suggest a CDR3-independent expansion of TRBV11-2+ T cells is a hallmark of MIS-C in children.
• These expanded T cells appear to lack specific recognition of SARS-CoV-2, pointing to a non-specific immune response.
• This research provides novel insights into the immunobiology of MIS-C.