Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function.
Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function.
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DOI：
10.4049/jimmunol.1301810
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发表时间：
2013-12-01
期刊：
影响因子：
--
通讯作者：
Petersen CA
中科院分区：
文献类型：
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作者：
Esch KJ;Juelsgaard R;Martinez PA;Jones DE;Petersen CA
婴儿利什曼原虫感染的控制依赖于Th1 CD4+ T细胞促进巨噬细胞对寄生虫的细胞内清除。临床内脏利什曼病（VL）期间CD4+ T细胞效应反应不足与IL-10的产生升高有关。在VL的主要国内宿主犬中，我们将CD4+和CD8+ T细胞衰竭的发生定义为抗原特异性增殖和IFNγ产生的显著逐步丧失，对应于VL症状的增加。衰竭与控制组和症状组之间表面表达程序性死亡1 （PD-1）的T细胞数量增加4倍有关。重要的是，耗尽的CD8+ T细胞群和较少程度的CD4+ T细胞在临床VL发病之前就存在。抗原刺激后VL耗竭T细胞体外未发生明显凋亡。PD-1配体抗体块，B7。H1促进CD4+和CD8+ T细胞功能的恢复，并显著增加共培养单核细胞源性吞噬细胞的活性氧产生。结果，这些吞噬细胞减少了寄生虫负荷。我们首次证明了泛t细胞，pd -1介导，VL期间的衰竭影响巨噬细胞活性氧中间体的产生。阻断PD-1通路可提高从临床VL犬身上分离的吞噬细胞清除细胞内寄生虫的能力。在有症状的犬利什曼病期间，T细胞耗竭对疫苗接种和治疗策略的反应有影响，以控制这一重要水库物种的婴儿利什曼病。
Control of Leishmania infantum infection is dependent upon Th1 CD4+ T cells to promote macrophage intracellular clearance of parasites. Deficient CD4+ T cell effector responses during clinical visceral leishmaniasis (VL) are associated with elevated production of IL-10. In the primary domestic reservoir of VL, dogs, we define occurrence of both CD4+ and CD8+ T cell exhaustion as a significant stepwise loss of antigen-specific proliferation and IFNγ production, corresponding to increasing VL symptomatology. Exhaustion was associated with a fourfold increase in the population of T cells with surface expression of Programmed Death 1 (PD-1) between control and symptomatic populations. Importantly, exhausted populations of CD8+ T cells and to a lesser extent CD4+ T cells were present prior to onset of clinical VL. VL exhausted T cells did not undergo significant apoptosis ex vivo after antigen stimulation. Antibody block of PD-1 ligand, B7.H1, promoted return of CD4+ and CD8+ T cell function and dramatically increased reactive oxygen species production in co-cultured monocyte-derived phagocytes. As a result, these phagocytes had decreased parasite load. We demonstrate for the first time that pan-T cell, PD-1-mediated, exhaustion during VL influenced macrophage reactive oxygen intermediate production. Blockade of the PD-1 pathway improved the ability of phagocytes isolated from dogs presenting with clinical VL to clear intracellular parasites. T cell exhaustion during symptomatic canine leishmaniasis has implications for the response to vaccination and therapeutic strategies for control of Leishmania infantum in this important reservoir species.