BCG vaccination elicits protection against Mtb infection mediated by two phases of T cell immunity

Vaccine development for tuberculosis is a global priority. Our studies using Collaborative Cross (CC) mice show that genetic diversity influences the efficacy of BCG, the most widely used TB vaccine. BCG vaccination of CC042 mice reduces their lung bacillary burden and increases their survival following low-dose aerosol Mycobacterium tuberculosis infection (MTBI), despite impaired T cell trafficking from a defective Itgal gene. Early protection requires the presence of T cells at the time of BCG vaccination but is not mediated by B cell or T cell recall responses following MTBI. In contrast, T cell depletion following BCG vaccination reduces survival after MTBI. Thus, CC042 mice reveal two phases of immunity induced by BCG that require T cells: an early phase mediated by innate responses and a later phase mediated by effector CD4 and/or CD8 T cells. Although measurement of vaccine-induced protection 30 days after MTBI is a standard measure of vaccine efficacy in the murine TB model, we find this time point is independent of memory T cells. Our results suggest that vaccine-elicited innate responses have a larger role in protection than previously considered. The concordance between lung CFU, pathology, and survival make CC042 mice a useful model for vaccine evaluation.