Evidence that recurrent Group A streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant Tfh cells

One Sentence Summary Recurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to Group A Streptococcus. ABSTRACT Recurrent Group A Streptococcus (GAS) tonsillitis (RT) is a common indication for pediatric tonsillectomy. ‘Strep throat’ is highly prevalent among children; yet, it is unknown why some children develop RT. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric GAS RT and non-RT tonsils. We observed significantly smaller germinal centers in GAS RT tonsils, and underrepresentation of GAS-specific germinal center follicular helper (GC Tfh) CD4+ T cells. RT children exhibited reduced antibody responses to GAS virulence factor SpeA. Risk and protective HLA Class II alleles for RT were identified. Finally, SpeA induced granzyme B+ GC Tfh cells in RT tonsils that had capacity to kill B cells. Together, these observations suggest that RT susceptibility can occur due to genetic differences that can result in aberrant GC Tfh cells and poor antibody responses to GAS SpeA.