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Toxoplasma gondii HLA-B(⁎)0702-restricted GRA7(20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8(+) T cells producing interferon-γ and reduces parasite burden in HLA-B(⁎)0702 mice

Cong, Hua and Mui, Ernest J and Witola, William H and Sidney, John and Alexander, Jeff and Sette, Alessandro and Maewal, Ajesh and El Bissati, Kamal and Zhou, Ying and Suzuki, Yasuhiro and Lee, Daniel and Woods, Stuart and Sommerville, Caroline and Henriquez, Fiona and Roberts, Craig and McLeod, Rima (2012) Toxoplasma gondii HLA-B(⁎)0702-restricted GRA7(20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8(+) T cells producing interferon-γ and reduces parasite burden in HLA-B(⁎)0702 mice. Human Immunology, 73 (1). pp. 1-10.

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Abstract

The ability of CD8(+) T cells to act as cytolytic effectors and produce interferon-γ (IFN-γ) was demonstrated to mediate resistance to Toxoplasma gondii in murine models because of the recognition of peptides restricted by murine major histocompatibility complex (MHC) class I molecules. However, no T gondii-specific HLA-B07-restricted peptides were proven protective against T gondii. Recently, 2 T gondii-specific HLA-B(⁎)0702-restricted T cell epitopes, GRA7(20-28) (LPQFATAAT) and GRA3(27-35) (VPFVVFLVA), displayed high-affinity binding to HLA-B(⁎)0702 and elicited IFN-γ from peripheral blood mononuclear cells of seropositive HLA-B(⁎)0702 persons. Herein, these peptides were evaluated to determine whether they could elicit IFN-γ in splenocytes of HLA-B(⁎)0702 transgenic mice when administered with adjuvants and protect against subsequent challenge. Peptide-specific IFN-γ-producing T cells were identified by enzyme-linked immunosorbent spot and proliferation assays utilizing splenic T lymphocytes from human lymphocyte antigen (HLA) transgenic mice. When HLA-B(⁎)0702 mice were immunized with one of the identified epitopes, GRA7(20-28) in conjunction with a universal CD4(+) T cell epitope (PADRE) and adjuvants (CD4(+) T cell adjuvant, GLA-SE, and TLR2 stimulatory Pam(2)Cys for CD8(+) T cells), this immunization induced CD8(+) T cells to produce IFN-γ and protected mice against high parasite burden when challenged with T gondii. This work demonstrates the feasibility of bioinformatics followed by an empiric approach based on HLA binding to test this biologic activity for identifying protective HLA-B(⁎)0702-restricted T gondii peptides and adjuvants that elicit protective immune responses in HLA-B(⁎)0702 mice.