Tuberculosis (TB) vaccine development is hindered by limited understanding of human immune responses to Mycobacterium tuberculosis. Using an aerosolized Mycobacterium bovis BCG human challenge model, we perform single-cell and bulk immune profiling of bronchoalveolar lavage and blood samples to define the temporal immune dynamics in BCG-naive individuals. Rapid changes in cellular composition and gene expression occur in both compartments, with TB-associated gene signatures evident on days 2 and 7 post-challenge. T cell receptor clones that expand in blood at day 7 persist in the lung mucosa until day 56 and are often detectable in blood before challenge. Pre-existing expanded clones are more enriched for activated CD4+ T cells and preferentially localize to the lung mucosa than newly expanded clones. Public expanded clones in the lung mucosa are validated as mycobacterial antigen-reactive using reporter T cells. These findings provide insights into mucosal and systemic immunity post-mycobacterial infection, informing TB vaccine design.