Gabrielle R. LeBlanc: No financial relationships to disclose
Introduction/Rationale: The use of antibiotics in early life is associated with recurrent respiratory infections in children. However, the mechanisms behind increased susceptibility to infection remain unclear. The development of mucosal associated invariant T (MAIT) cells is dependent on the recognition of derivatives of riboflavin produced by microbes during early life. Therefore, we hypothesized that use of antibiotics during this period would deplete microbes that synthesize these metabolites and disrupt MAIT cell development and related immunity to infections.
Methods: In vitro screening of antibiotics that are frequently prescribed to human neonates was used to identify drugs which inhibit the growth of riboflavin-synthesizing commensal bacteria. Antibiotics were administered to mice during specific developmental windows to identify the impact on MAIT cell abundances at barrier tissues and in the thymus. Infection models with Francisella tularensis were utilized to characterize the effect of impaired MAIT cell development. Models of probiotic therapy and adoptive cell transfer were explored as means to restore MAIT cell-mediated immunity.
Results: Administration of antibiotics to mice revealed a specific window when MAIT cell development is most affected by the depletion of riboflavin-synthesizing commensals. This resulted in a long-lasting reduction in MAIT cell abundance and an increased susceptibility to pneumonia, similar to what was observed in MAIT cell-deficient Mr1−/− mice, indicating the adverse impact on immunity is mediated by MAIT cells. Impaired MAIT cell development and immune responses were rescued by concomitant delivery of a probiotic during antibiotic treatment in early life or adoptive transfer of MAIT cells.
Conclusion: This work establishes a mechanism by which temporary disruption of the developing microbiome affects immune responses to infections later in life, highlighting the need for discriminant use of antibiotics and optimized probiotic therapies.
