HLA-A2.1 is one of the most common MHC class I molecules in humans. To examine whether antigen presentation by the HLA-A2.1 activates the protective immunity against reactivation of cerebral infection with Toxoplasma gondii, C57BL/6-background HLA-A2.1-transgenic and wild-type (WT) mice were infected and treated with sulfadiazine beginning at 7 days after infection for 10 days to control tachyzoite proliferation and establish chronic infection in their brains. Due to the genetic susceptibility of C57BL/6 mice to chronic T. gondii infection, these mice develop reactivation of the infection after discontinuation of sulfadiazine treatment. One month after discontinuation of sulfadiazine, mRNA levels for tachyzoite-specific SAG1 and numbers of the foci associated tachyzoites were significantly less in the brains of the HLA-A2.1-transgenic than WT mice. Greater numbers of IFN-g-producing CD8+ T cells were detected in the spleens of infected transgenic than WT mice, and CD8+ T cells from the former produced markedly greater amounts of IFN-gthan the T cells from the latter in response to tachyzoite antigens in vitro. When their CD8+ T cells were systemically transferred to infected immunodeficient NSG mice expressing the HLA-A2.1, the CD8+ T cells from HLA-A2.1-transgenic mice inhibited reactivation of the cerebral infection in the recipients more efficiently than did the WT T cells. Furthermore, the inhibition of reactivation of the infection by CD8+ T cells from the transgenic mice was associated with increased cerebral expression of IFN-g and effector molecules against tachyzoites in the recipients when compared to the WT CD8+ T cell recipients. Thus, the human HLA-A2.1 is able to effectively activate IFN-g production of CD8+ T cells against T. gondii tachyzoites and confer a potent protection against reactivation of cerebral infection with this parasite through the CD8+ T cells activation.