In mice, susceptibility to Leishmania major is associated with the early expansion of T helper 2 cells (T(H)2) cells, but nothing is known of the specificity of these cells. A previously identified antigen, Leishmania homolog of receptors for activated C kinase (LACK), was found to be the focus of this initial response. Mice made tolerant to LACK by the transgenic expression of the antigen in the thymus exhibited both a diminished T(H)2 response and a healing phenotype. Thus, T cells that are activated early and are reactive to a single antigen play a pivotal role in directing the immune response to the entire parasite.