DiverseStreptococcus pneumoniaestrains drive a MAIT cell response through MR1-dependent and cytokine-driven pathways

Mucosal Associated Invariant T (MAIT) cells represent an innate T cell population of emerging significance. These abundant cells can recognize ligands generated by microbes utilizing the riboflavin synthesis pathway, presented via the major histocompatibility complex (MHC) class I-related molecule MR1 and binding of specific T cell receptors (TCR). They also possess an innate functional programme allowing microbial sensing in a cytokine-dependent, TCR-independent manner.Streptococcus pneumoniaeis a major human pathogen that is also associated with commensal carriage, thus host control at the mucosal interface is critical. The recognition of S.pneumoniaestrains by MAIT cells has not been defined, nor have the genomics and transcriptomics of the riboflavin operon (Rib genes). We examined the expression of Rib genes in S.pneumoniaeat rest and in response to metabolic stress and linked this to MAIT cell activationin vitro.We observed robust recognition ofS. pneumoniaestrains at rest and following stress, using both TCR-dependent and TCR-independent pathways. The pathway used was highly dependent on the antigen-presenting cell, but was maintained across a wide range of clinically-relevant strains. The riboflavin operon was highly conserved across a range of 571 S.pneumoniaefrom 39 countries dating back to 1916, and different versions of the riboflavin operon were also identified in relatedStreptococcusspecies. These data indicate an important functional relationship between MAIT cells and S.pneumoniae,which may be tuned by local factors, including the metabolic state of the organism and the antigen-presenting cell that it encounters.Author SummaryStreptococcus pneumoniaeis the leading cause of bacterial pneumonia, causes invasive diseases such as meningitis and bacteraemia, and is associated with significant morbidity and mortality, particularly in children and the elderly. Here, we demonstrate that a novel T cell population called Mucosal-associated invariant T (MAIT) cells is able to respond to a diverse range of S.pneumoniaestrains. We found that this response was dependent on the T cell receptor (which recognises metabolites of the bacterial riboflavin biosynthesis pathway), cytokines, and the type of antigen-presenting cell. A population genomics approach was also used to assess the prevalence and diversity of the genes encoding the riboflavin biosynthesis pathway among a large and diverse collection of S.pneumoniae.These genes were highly conserved across a range of 571 S.pneumoniaefrom 39 countries dating back to 1916, and was also present in other relatedStreptococcusspecies. Given the low levels of MAIT cells in neonates and MAIT cell decline in the elderly, both of whom are at the highest risk of invasive pneumococcal disease, further understanding of the functional role of MAIT cells in host defense against this major pathogen may allow novel therapeutics or vaccines to be designed.