TB is a contagious lung disease caused by Mycobacterium tuberculosis (Mtb). The only approved vaccine for TB prevention is BCG, however, its efficacy among adults varies from 0-70%. To improve TB prevention, we need to better understand how vaccines work. How genetic variation affects BCG’s ability to protect is incompletely understood. To mimic genetic variation, we have used the Collaborative Cross (CC) resource of genetically diverse inbred mice. One of these, the CC042 strain is susceptible to Mtb infection due to its loss of lymphocyte function-associated antigen 1 (LFA-1) expression, which results in defective T cell trafficking to the lung. Despite this defect in T cell recruitment, BCG vaccination protects CC042 mice against TB. We hypothesized that this defect in T cell immunity reveals alternative mechanisms of protective immunity against Mtb.

In this dissertation I investigate the requirement for LFA-1 in generating immunity to BCG and Mtb using LFA-1-deficient CD11a–/– and CC042 mice. I find that adaptive immunity to BCG occurs independently of LFA-1. BCG vaccination provides lasting protection to CC042 mice against Mtb infection by reducing their lung disease and extends their lifespan. We discovered that BCG-induced protection of CC042 is maintained even when lymphocyte migration is disrupted, and neither concurrent depletion of memory T nor B cells disrupt BCG-elicited protection against Mtb infection in CC042 mice. However, memory T cells were crucial for long-term protection of CC042 mice. These findings provide key insights into different phases of protective immunity that are generated following BCG vaccination.