We investigated the regulation of T-cell homing receptors in infectious disease by evaluating the cutaneous lymphocyte antigen (CLA) in human leprosy. We found that CLA-positive cells were enriched in the infectious lesions associated with restricting the growth of the pathogen Mycobacterium leprae, as assessed by the clinical course of infection. Moreover, CLA expression on T cells isolated from the peripheral blood of antigen-responsive tuberculoid leprosy patients increased in the presence of M. leprae (2·4-fold median increase; range 0·8–6·1, n = 17), but not in unresponsive lepromatous leprosy patients (1·0-fold median increase; range 0·1–2·2, n = 10; P < 0·005). Mycobacterium leprae specifically up-regulated the skin homing receptor, CLA, but not α4/β7, the intestinal homing receptor, which decreased on T cells of patients with tuberculoid leprosy after antigen stimulation (2·2-fold median decrease; range 1·6–3·4, n = 3). Our data indicate that CLA expression is regulated during the course of leprosy infection and suggest that T-cell responsiveness to a microbial antigen directs antigen-specific T cells to the site of infection.