Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis.
Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis.
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DOI：
10.1371/journal.pntd.0000480
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发表时间：
2009-07-14
影响因子：
3.8
通讯作者：
Kropf P
中科院分区：
文献类型：
--
作者：
Modolell M;Choi BS;Ryan RO;Hancock M;Titus RG;Abebe T;Hailu A;Müller I;Rogers ME;Bangham CR;Munder M;Kropf P
辅助性T细胞（Th）1和Th 2细胞反应之间的平衡是实验性利什曼病结果的主要决定因素，但极化的Th 1或Th 2反应不足以解释愈合或不愈合。在这里，我们表明，高的β-淀粉酶活性，一个标志性的非愈合性疾病，主要是局部表达的病理部位。高精氨酸酶活性导致L-精氨酸的局部消耗，这损害了病变中T细胞增殖和产生干扰素-γ的能力，而局部引流淋巴结中的T细胞反应正常。通过化疗诱导的愈合，导致了抑制酶活性的控制和局部免疫抑制的逆转。此外，竞争性抑制的酶，以及补充L-精氨酸恢复T细胞效应功能和减少病变部位的病理和寄生虫的生长。这些结果表明，在不愈合的利什曼病中，精氨酸酶诱导的L-精氨酸耗竭导致T细胞应答受损。我们的研究结果确定了一种新的机制，在利什曼病，有助于未能治愈持续性病变，并提出了新的治疗方法。 利什曼原虫是专性细胞内病原体，主要侵入巨噬细胞。巨噬细胞通过T细胞衍生的信号的指令是控制寄生虫生长所必需的。在这里，我们表明，在利什曼原虫感染的巨噬细胞中诱导的一种酶，在不愈合病变的病理部位高度表达，并导致L-精氨酸的局部消耗，L-精氨酸是一种对有效的T细胞反应至关重要的氨基酸。L-精氨酸的这种局部减少损害了病变中T细胞增殖和产生干扰素-γ的能力，干扰素-γ是杀死寄生虫所需的信号之一。通过药物治疗治愈利什曼原虫感染伴随着酶活性的降低和T细胞效应功能的恢复。此外，抑制寄生虫酶以及注射L-精氨酸可逆转免疫抑制，并导致更有效地控制寄生虫复制。我们的研究结果确定了一种新的机制，占无效的T细胞反应在不愈合的利什曼病。
The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy. Leishmania parasites are obligate intracellular pathogens that predominantly invade macrophages. Instruction of macrophages by T cell-derived signals is required to control parasite growth. Here we show that arginase, an enzyme induced in Leishmania-infected macrophages, is highly expressed at the site of pathology in nonhealing lesions and causes local depletion of L-arginine, an amino acid that is essential for efficient T cell responses. This local reduction in L-arginine impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, one of the signals required for parasite killing. Cure of Leishmania infection by drug treatment is accompanied by a reduction in arginase activity and restoration of T cell effector functions. Furthermore, inhibition of arginase, as well as injection of L-arginine, reverses immunosuppression and results in more efficient control of parasite replication. Our results identify a novel mechanism accounting for ineffective T cell responses in nonhealing leishmaniasis.
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影响因子：
3.7
作者：
Kurkjian, Katie M.;Mahmutovic, Aidaj.;Secor, W. Evan
通讯作者：
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