Our previous studies identified that the amino-terminus region (amino acids 41-152) of dense granule protein 6 (GRA6Nt) of Toxoplasma gondii potently activate CD8+ T cells capable of removing tissue cysts in BALB/c mice genetically resistant to this infection. In the present study, we examined whether GRA6Nt is able to activate anti-cyst CD8+ T cells through antigen presentation by the HLA-A2.1, one of the three most common MHC class I molecules in humans. HLA-A2.1-transgenic and wild-type (WT) control mice were immunized intraperitoneally with 50 mg of recombinant GRA6Nt (rGRA6Nt) twice with a four-week interval. Two weeks after the 2nd immunization, CD8+ cells from the immunized HLA-A2.1-transgenic mice, but not WT mice, secreted large amounts of perforin and granzyme B in response to GRA6Nt through antigen presentation by HLA-A2.1 in vitro. When those CD8+ T cells were transferred into chronically infected HLA-A2.1-expressing NSG mice deficient in T cells, cerebral cyst burden of the recipients of HLA-A2.1-transgenic T cells, but not of WT T cells, became significantly less than that of control mice with no cell transfer. Furthermore, the significant reduction of the cyst burden by a transfer of the HLA-A2.1-transgenic CD8+ immune T cells required an expression of HLA-A2.1 in the recipient NSG mice. Thus, antigen presentation of GRA6Nt by human HLA-A2.1 is able to activate anti-cyst CD8+ T cells that eliminate T. gondiicysts through antigen presentation by the HLA-A2.1.