Project Summary It has remained a longstanding mystery why some children are susceptible to recurrent tonsillitis. Tonsillectomies are the most common pediatric surgery in America, with recurrent tonsillitis associated with S. pyogenes (group A streptococcus, GAS) being a primary cause. We have preliminary data that there is an immunological basis for recurrent streptococcal tonsillitis. Antibody responses are a central part of the immune system. T follicular helper CD4 T cells (Tfh cells) are required for germinal centers, and thus the majority of high affinity antibody responses. Tfh cells have important roles in protection from infectious diseases. Much remains to be learned about Tfh cells. We have developed a novel method for quantifying pathogen-specific Tfh cells, the activation immune marker (AIM) assay. The goal of this proposal is to ascertain the immunologic mechanisms tied to recurrent strep throat, and the GAS virulence factors that cause recurrent tonsillitis disease. Completion of this study could help identify children who are likely to be susceptible to recurrent strep throat, and mechanistics studies propsed herein could allow for rational design of countermeasures to prevent the disease in the future.