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.