Division of Immunology and Pathogenesis, Department of Molecular and Cellular Biology, University of California, Berkeley, California, USA.
Infect Immun. 2012 Sep;80(9):3279-88. doi: 10.1128/IAI.00425-12. Epub 2012 Jul 9.
The apicomplexan parasite Toxoplasma gondii can cause severe disease in immunocompromised individuals. Previous studies in mice have focused largely on CD8(+) T cells, and the role of CD4 T cells is relatively unexplored. Here, we show that immunization of the C57BL/6 strain of mice, in which the immunodominant CD8 T cell response to the parasite dense-granule protein GRA6 cannot be generated, leads to a prominent CD4 T cell response. To identify the CD4 T cell-stimulating antigens, we generated a T. gondii-specific, lacZ-inducible, CD4 T cell hybridoma and used it as a probe to screen a T. gondii cDNA library. We isolated a cDNA encoding a protein of unknown function that we call CD4Ag28m and identified the minimal peptide, AS15, which was presented by major histocompatibility complex (MHC) class II molecules to the CD4 T cells. Immunization of mice with the AS15 peptide provided significant protection against subsequent parasite challenge, resulting in a lower parasite burden in the brain. Our findings identify the first CD4 T cell-stimulating peptide that can confer protection against toxoplasmosis and provide an important tool for the study of CD4 T cell responses and the design of effective vaccines against the parasite.
刚地弓形虫是一种专性细胞内寄生的顶复门原虫，能够引起免疫抑制个体的严重疾病。先前在小鼠中的研究主要集中在 CD8(+) T 细胞上，而 CD4 T 细胞的作用相对未被探索。在这里，我们表明，对 C57BL/6 品系小鼠进行免疫接种，会导致明显的 CD4 T 细胞反应，而该品系小鼠无法产生针对寄生虫致密颗粒蛋白 GRA6 的免疫优势 CD8 T 细胞反应。为了鉴定 CD4 T 细胞刺激抗原，我们生成了一种 T. gondii 特异性、β-半乳糖苷酶诱导、CD4 T 细胞杂交瘤，并将其用作探针来筛选 T. gondii cDNA 文库。我们分离出了一个编码未知功能蛋白的 cDNA，我们称之为 CD4Ag28m，并鉴定出最小的肽段 AS15，它由主要组织相容性复合体（MHC）II 类分子呈递给 CD4 T 细胞。用 AS15 肽对小鼠进行免疫接种可提供针对寄生虫后续攻击的显著保护，导致大脑中的寄生虫负荷降低。我们的发现确定了第一个可赋予抗弓形体病保护作用的 CD4 T 细胞刺激肽，并为 CD4 T 细胞反应的研究和针对寄生虫的有效疫苗设计提供了重要工具。
