T and B cells recognize splicing-derived neutrophil neoantigens in lupus.

Neutrophils from patients with systemic lupus erythematosus (SLE) contain many aberrantly spliced transcripts whose predicted translation yields novel amino-acid sequences recognized as neoantigens.

• Why it matters: Proteome diversity from alternative splicing can create tumour neoantigens, but it was unclear whether similar splicing-derived neoantigens arise in SLE and engage adaptive immunity.
• What they did: The study detected 21 peptides from novel amino-acid sequences on class I major histocompatibility complex molecules by mass spectrometry, then co-cultured patient T cells with overlapping 15-mer peptide sets.
• The result: Overlapping peptide sets expanded CD4+ and CD8+ T cells that rapidly secreted interferon-γ, and TCR sequencing plus re-expression transferred neoantigen reactivity; SLE serum IgG autoantibodies also recognized epitopes within the novel sequences.