The macrophage natural resistance gene. Lsh, regulates the ability of a selective population of tissue macrophages to control intracellular multiplication of Leishmania donovani by a T-cell independent mechanism. We show here, using mice congenic for Lsh, that this gene also contributes to the acquisition of T-cell-mediated immunity. Whereas both resistant and susceptible mice generate equivalent primary T-cell responses to infection, resistant mice show a rapid increase in accessory cell activity, allowing for greater subsequent T-cell expansion. This change in accessory cell function correlates with increased class II antigen expression relative to susceptible mice, both in vivo during early infection and in vitro in response to induction by interferon-gamma (IFN-gamma). Differences in vitro were independent of, but differentially affected by, amastigote infection.