The role of regulatory T cells in early life immunity to BCG: influence of exposure to environmental mycobacteria

BCG is the only licensed vaccine against tuberculosis (TB), yet its protective efficacy is variable. Exposure to non-tuberculous mycobacteria (NTM) has been shown to render BCG less effective. It was therefore hypothesised that exposure to NTM in early life may attenuate the immunogenicity of BCG, and that regulatory T cells (Tregs) may contribute to this reduced response. Neonates were recruited at birth (n = 103) and randomised to receive BCG vaccine at birth or at 4½ months of age. Blood was collected at birth, 4½- and 9- months of age and immune responses were assessed by flow cytometry and multiplex bead array. Exposure to NTM prior to BCG vaccination elicited Th1 and Th2 responses to PPD-tuberculin at 4½ months, including IL-10 induction that was not observed in those vaccinated at birth. Higher IFNɣ production 4½ months post vaccination was observed in children vaccinated at birth compared to 4½ months of age. The results support the starting hypothesis and suggest that while FOXP3+ Tregs are not involved in the attenuated response, NTM induced IL-10-producing Tregs may be responsible for the reduced IFNɣ reactivity. Interestingly IL-13 was induced by BCG vaccination at both time points and was sustained until 9 months of age in those vaccinated at birth. IFNɣ and IL-10 both correlated with tuberculin skin test (TST) reactivity. The data suggests that IFNɣ may initiate the response, but IL-10 controls the induration. It was also clear that higher ‘cut offs’ for the TST are more appropriate for defining possible M.tb infection in BCG vaccinated children in this environment. Overall the results suggest that exposure to NTM attenuated the pro-inflammatory response when vaccination was delayed. Vaccination at birth induced a mixed Th1/Th2 response at 4½ months, but only the Th2 response was sustained at 9 months. Furthermore, IL-10 appears to play a critical role in regulating mycobacterial immunity.