Immune responses rely on an intricate system of adhesion molecules to coordinate the homing and retention of lymphocytes in both secondary lymphoid tissues and at sites of infection. To define the events associated with pulmonary immune responses, the expression of endothelial addressins and integrins on T cells was analyzed during Mycobacterium tuberculosis infection. In infected lung, expression of endothelial VCAM-1, but not mucosal addressin cell adhesion molecule-1, was up-regulated from 4 wk postinfection and persisted to at least 12 wk. Subsequent analysis of the corresponding integrins expressed on lung CD4+ and CD8+ T cells revealed an accumulation of β 1 high/β 7−/low, and to a lesser extent β 7 high, integrin-expressing T cells during infection. Examination of integrin heterodimers showed that while α 4 integrin was predominantly expressed on β 1 high/β 7−/low cells, α E integrin was primarily associated with β 7 high. The majority of activated/memory T cells recruited during infection expressed high levels of β 1 integrin and undetectable or low levels of β 7 integrin. These T cells were capable of producing IFN-γ, a cytokine crucial for controlling M. tuberculosis infection. Rapid expansion of β 1 high, β 7−, and β 7 high T cell populations in the lung upon secondary mycobacterial infection indicates the participation of these populations in the acquired immune response to the infection. Furthermore, treatment of infected mice with mAb to α 4 or α 4 β 7 integrin led to a reduction in lymphocytes and increase in granulocytes in the pulmonary infiltrate. These results reveal a crucial role for adhesion molecules in the generation of an effective pulmonary immune response to M. tuberculosis infection.