Major histocompatibility complex (MHC) class II (A beta) knockout mice were vaccinated with ts-4, an attenuated mutant strain of Toxoplasma gondii, which in normal animals induces strong T cell immunity mediated by interferon gamma (IFN-gamma). After challenge with the lethal parasite strain RH, the knockout mice displayed decreased resistance consistent with absence of CD4+ effectors. Nevertheless, these animals generated CD8+ lymphocyte effectors capable of mediating partial protection through IFN-gamma secretion. Moreover, in vivo neutralization experiments indicated that the development of resistance in knockout mice depends on CD4+ cells as well as interleukin 2 (IL-2). The identity of the IL-2-producing protective cell population was further characterized as CD4+, NK1.1+ by in vitro depletion studies and reverse transcriptase-PCR analysis of fluorescence-activated cell sorter (FACS)-purified CD4+ NK1.1+ T lymphocytes. These results demonstrate that in the absence of conventional MHC class II-restricted CD4+ T lymphocytes, CD8 priming persists and mediates partial protective immunity to T. gondii. Moreover, the data argue that CD4+, NK1.1+ cells, previously implicated in the initiation of T helper cell 2 (Th2) responses through their production of IL-4, can also play a role as alternative IL-2-secreting helper cells in Th1-mediated host resistance to infection.