Antibiotic use in early life impairs MAIT cell-mediated immunity

While neonatal antibiotic use is associated with increased susceptibility to infection, the reasons why remain unclear. Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. We have shown that exposure to these microbial products in early life imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate MAIT cell development and impair subsequent immune responses. Through an in vitro screen, we identified antibiotics that deplete riboflavin-synthesizing commensals. Administration to mice revealed a brief period of susceptibility which impaired MAIT cell development and corresponded to enrichment of riboflavin synthesizers within the intestinal microbiome of untreated animals. Early-life antibiotic treatment decreased MAIT cell abundance in adult mice, rendering these animals more susceptible to pneumonia. Immunity was unaltered in MAIT cell-deficient Mr1^-/- mice, indicating that the detrimental effects of early antibiotic use were mediated by MAIT cells. Administration of a riboflavin-synthesizing commensal was sufficient to restore MAIT cell development and immunity. Our work demonstrates that depletion of riboflavin-synthesizing commensals in early life can adversely affect immunity to subsequent infections, necessitating the development of novel probiotics.