Stone Geoffrey W, Barzee Suzanne, Snarsky Victoria, Spina Celsa A, Lifson Jeffrey D, Pillai Vinod Kumar Bhaskara, Amara Rama Rao, Villinger François, Kornbluth Richard S
Department of Medicine, University of California, San Diego, La Jolla, California 92093-0679, USA.
Clin Vaccine Immunol. 2006 Nov;13(11):1223-30. doi: 10.1128/CVI.00198-06. Epub 2006 Sep 20.
CD40 ligand (CD40L) and GITR ligand (glucocorticoid-induced tumor necrosis factor receptor-related protein ligand [GITRL]) are tumor necrosis factor superfamily molecules that can be used as vaccine adjuvants. In a previous human immunodeficiency virus (HIV) DNA vaccine study in mice, we found that plasmids expressing multimeric soluble forms of trimeric CD40L (i.e., many trimers) were stronger activators of CD8(+) T-cell responses than were single-trimer soluble forms or the natural membrane-bound molecule. This report describes similar multimeric soluble molecules that were constructed for studies in macaques. Both two-trimer and four-trimer forms of macaque CD40L were active in B-cell proliferation assays using macaque and human cells. With human cells, four-trimer macaque GITRL costimulated CD4(+) T-cell proliferation and abrogated the immunosuppressive effects of CD4(+) CD25(+) regulatory T cells on a mixed leukocyte reaction. These molecular adjuvants provide new tools for vaccine development in the simian immunodeficiency virus system and other macaque models.
CD40配体（CD40L）和糖皮质激素诱导的肿瘤坏死因子受体相关蛋白配体（GITRL）是可作为疫苗佐剂的肿瘤坏死因子超家族分子。在之前一项针对小鼠的人类免疫缺陷病毒（HIV）DNA疫苗研究中，我们发现，表达三聚体CD40L多聚体可溶性形式（即多个三聚体）的质粒比单三聚体可溶性形式或天然膜结合分子更能有效激活CD8(+) T细胞反应。本报告描述了为猕猴研究构建的类似多聚体可溶性分子。猕猴CD40L的二聚体和四聚体形式在使用猕猴和人类细胞的B细胞增殖试验中均具有活性。对于人类细胞，四聚体猕猴GITRL共刺激CD4(+) T细胞增殖，并消除了CD4(+) CD25(+) 调节性T细胞对混合淋巴细胞反应的免疫抑制作用。这些分子佐剂为猿猴免疫缺陷病毒系统和其他猕猴模型中的疫苗开发提供了新工具。
