Anti-CD25 Treatment Depletes Treg Cells and Decreases Disease Severity in Susceptible and Resistant Mice Infected with Paracoccidioides brasiliensis
Anti-CD25 Treatment Depletes Treg Cells and Decreases Disease Severity in Susceptible and Resistant Mice Infected with Paracoccidioides brasiliensis
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DOI：
10.1371/journal.pone.0051071
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发表时间：
2012-11-30
期刊：
影响因子：
3.7
通讯作者：
Calich, Vera L. G.
中科院分区：
文献类型：
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作者：
Felonato, Maira;Pina, Adriana;Calich, Vera L. G.
调节性 T (Treg) 细胞对于控制免疫和过度组织病理学至关重要。在副球孢子菌病（拉丁美洲的一种地方性真菌病）中，控制这种感染的进行性和消退性形式的免疫调节机制知之甚少。由于其对 Treg 细胞的调节活性，我们研究了抗 CD25 治疗在感染巴西副球孢子虫的耐药 (A/J) 和易感 (B10.A) 小鼠肺部感染过程中的影响。我们证实，与易感 B10.A 小鼠相比，耐药 A/J 小鼠产生了更多数量和更强的 Treg 细胞。与B10.A细胞相比，A/J小鼠的CD4(+)CD25(+)Foxp3(+) Treg细胞表达更高水平的CD25、CTLA4、GITR、Foxp3、LAP以及细胞内IL-10和TGF-β。在耐药小鼠和易感小鼠中，抗CD25治疗均减少了CD4(+)CD25(+)Foxp3(+) Treg细胞数量，损害了吲哚胺2,3-双加氧酶的表达，并导致肺、肝和脾中的真菌负荷减少。在 A/J 小鼠中，抗 CD25 治疗导致 T 细胞免疫力早期增强，活化的 CD4+ 和 CD8+ T 细胞、巨噬细胞和树突状细胞流入肺部的数量增加就证明了这一点。在后期，轻度感染与炎症反应减少和 Th1/Th2/Th17 细胞因子产生增加相关。在 B10.A 小鼠中，抗 CD25 治疗并未改变炎症反应，但增加了杀菌机制和 Th1/Th2/Th17 细胞因子的晚期分泌。重要的是，在这两种小鼠品系中，CD25+细胞的早期消耗导致组织病理学不那么严重，并消除了在易感小鼠中观察到的死亡率增加的现象。总之，这项研究首次证明抗 CD25 治疗对副球孢子菌病的进展和消退形式有益，可能是由于抗 CD25 介导的 Treg 细胞减少，因为这些细胞对耐药小鼠的早期 T 细胞反应和易感小鼠的真菌细胞清除机制具有抑制作用。
Regulatory T (Treg) cells are fundamental in the control of immunity and excessive tissue pathology. In paracoccidioidomycosis, an endemic mycosis of Latin America, the immunoregulatory mechanisms that control the progressive and regressive forms of this infection are poorly known. Due to its modulatory activity on Treg cells, we investigated the effects of anti-CD25 treatment over the course of pulmonary infection in resistant (A/J) and susceptible (B10.A) mice infected with Paracoccidioides brasiliensis. We verified that the resistant A/J mice developed higher numbers and more potent Treg cells than susceptible B10.A mice. Compared to B10.A cells, the CD4(+)CD25(+)Foxp3(+) Treg cells of A/J mice expressed higher levels of CD25, CTLA4, GITR, Foxp3, LAP and intracellular IL-10 and TGF-beta. In both resistant and susceptible mice, anti-CD25 treatment decreased the CD4(+)CD25(+)Foxp3(+) Treg cell number, impaired indoleamine 2,3-dioxygenase expression and resulted in decreased fungal loads in the lungs, liver and spleen. In A/J mice, anti-CD25 treatment led to an early increase in T cell immunity, demonstrated by the augmented influx of activated CD4(+) and CD8(+) T cells, macrophages and dendritic cells to the lungs. At a later phase, the mild infection was associated with decreased inflammatory reactions and increased Th1/Th2/Th17 cytokine production. In B10.A mice, anti-CD25 treatment did not alter the inflammatory reactions but increased the fungicidal mechanisms and late secretion of Th1/Th2/Th17 cytokines. Importantly, in both mouse strains, the early depletion of CD25(+) cells resulted in less severe tissue pathology and abolished the enhanced mortality observed in susceptible mice. In conclusion, this study is the first to demonstrate that anti-CD25 treatment is beneficial to the progressive and regressive forms of paracoccidioidomycosis, potentially due to the anti-CD25-mediated reduction of Treg cells, as these cells have suppressive effects on the early T cell response in resistant mice and the clearance mechanisms of fungal cells in susceptible mice.