Immunology and Infection Laboratory, Queensland Institute of Medical Research and The Australian Center for Vaccine Development, Queensland Institute of Medial Research, Herston, Queensland, Australia.
J Immunol. 2010 Mar 1;184(5):2583-92. doi: 10.4049/jimmunol.0903080. Epub 2010 Feb 5.
Chronic infectious diseases and cancers are often associated with suboptimal effector T cell responses. Enhancement of T cell costimulatory signals has been extensively studied for cancer immunotherapy but not so for the treatment of infectious disease. The few previous attempts at this strategy using infection models have lacked cellular specificity, with major immunoregulatory mechanisms or innate immune cells also being targeted. In this study, we examined the potential of promoting T cell responses via the glucocorticoid-induced TNF receptor (GITR) family-related protein in a murine model of visceral leishmaniasis. GITR stimulation during established infection markedly improved antiparasitic immunity. This required CD4(+) T cells, TNF, and IFN-gamma, but crucially, was independent of regulatory T (Treg) cells. GITR stimulation enhanced CD4(+) T cell expansion without modulating Treg cell function or protecting conventional CD4(+) T cells from Treg cell suppression. GITR stimulation substantially improved the efficacy of a first-line visceral leishmaniasis drug against both acute hepatic infection and chronic infection in the spleen, demonstrating its potential to improve clinical outcomes. This study identifies a novel strategy to therapeutically enhance CD4(+) T cell-mediated antiparasitic immunity and, importantly, achieves this goal without impairment of Treg cell function.
慢性传染病和癌症通常与效应 T 细胞反应不佳有关。增强 T 细胞共刺激信号已被广泛研究用于癌症免疫治疗，但在治疗传染病方面却没有得到充分研究。以前在使用感染模型进行这项策略的少数尝试中，缺乏细胞特异性，主要的免疫调节机制或先天免疫细胞也成为了靶点。在这项研究中，我们在内脏利什曼病的小鼠模型中研究了通过糖皮质激素诱导的 TNF 受体（GITR）家族相关蛋白促进 T 细胞反应的潜力。在已建立的感染期间刺激 GITR 显著改善了抗寄生虫免疫。这需要 CD4(+)T 细胞、TNF 和 IFN-γ，但至关重要的是，这与调节性 T (Treg)细胞无关。GITR 刺激增强了 CD4(+)T 细胞的扩增，而不调节 Treg 细胞的功能，也不能保护常规 CD4(+)T 细胞免受 Treg 细胞的抑制。GITR 刺激显著提高了一线内脏利什曼病药物对急性肝感染和脾脏慢性感染的疗效，表明其有潜力改善临床结果。这项研究确定了一种新的策略，可治疗性地增强 CD4(+)T 细胞介导的抗寄生虫免疫，重要的是，实现这一目标而不损害 Treg 细胞的功能。
