Rapid mobilization of antigen-specific T helper (Th) type 1-like CD4(+) T cells to the lung appears to be critically important for control of the respiratory pathogen Mycobacterium tuberculosis (M. tb), and for protection against pulmonary tuberculosis, the most contagious form of the disease. Accordingly, the preferential circulation of memory lymphocytes back to the tissues in which they first encountered antigen (i.e., "homing") may underlie the limited efficacy of current intradermal vaccination with the M. bovis strain bacillus Calmette-Guerrin. We previously developed a method of bronchoscopic antigen challenge with purified protein derivative of M. tb (PPD) to model local recall responses of healthy PPD-positive individuals who were infected via respiratory exposure to M. tb. Bronchoscopic challenge with PPD results in recruitment of additional antigen-specific Th1-like cells into challenged lung segments of healthy M. tb-infected individuals but not those of PPD-negative control subjects. In this study, we assessed the role of homing molecule expression in localization of M. tb-specific recall responses to the lung. Compared with peripheral blood, baseline bronchoalveolar lavage is significantly enriched for CD4(+) T cells expressing the α4β1 integrin homing molecule. This skewing is continued after PPD-induced recruitment of CD4(+) T cells, and is even more pronounced for recruited CD4(+) cells that display PPD-specific production of IFN-γ, of which over 83% express α4β1. Expression of the α4β1 integrin, therefore, appears likely to optimize localization of M. tb-specific Th1-like recall responses to the human lung.