CCR5-dependent regulatory T cell migration mediates fungal survival and severe immunosuppression
CCR5-dependent regulatory T cell migration mediates fungal survival and severe immunosuppression
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DOI：
10.4049/jimmunol.180.5.3049
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Silva, Joao S.
中科院分区：
文献类型：
--
作者：
Moreira, Ana Paula;Cavassani, Karen Angelica;Silva, Joao S.
副球孢子菌病是一种使人衰弱的肺部真菌病，由二型真菌巴西副球孢子菌引起。感染导致肉芽肿的形成，肉芽肿中含有活酵母细胞，这些细胞是疾病再激活的真菌来源。由于CD 4（+）CD 25（+）调节性T细胞（Treg）存在于副球孢子菌病患者的病变中，Treg细胞的迁移依赖于轴趋化因子-趋化因子受体，并且在巴西假单胞菌诱导的病变中产生CCR 5配体，因此我们研究了CCR 5在控制感染中的作用。结果显示，CCR 5（-/-）小鼠在控制真菌生长和传播方面更有效，并且表现出比野生型（WT）小鼠更小的肉芽肿。在缺乏CCR 5的情况下，肉芽肿中表达Foxp 3、糖皮质激素诱导的TNFR（GITR）、CD 103、CD 45（低）和CTLA-4的CD 4（+）CD 25（+）T细胞的百分比显著降低。有趣的是，巴西疟原虫感染导致WT小鼠而非CCR 5（-/-）小鼠中不存在响应于Con A的T细胞增殖，CCR 5（-/-）小鼠被抗CTLA-4 mAb和抗GITR mAb消除。此外，从感染的WT至感染的CCR 5（-/-）小鼠的CD 4（+）CD 25（+）而非CD 4（+）CD 25（-）T细胞的过继转移导致真菌负荷的显著增加。总的来说，CCR 5是Treg细胞迁移到巴西疟原虫感染部位的关键受体，导致效应免疫应答的下调和真菌在肉芽肿中的长期存在。因此，严格控制Treg细胞向肉芽肿性病变的迁移可能是避免疾病恶化和再活化的重要机制。
Paracoccidioidomycosis, a debilitating pulmonary mycosis, is caused by the dimorphic fungus Paracoccidioides brasiliensis. The infection results in the formation of granulomas containing viable yeast cells that are the fungal sources for disease reactivation. Because CD4(+)CD25(+) regulatory T cells (Tregs) are in the lesions of patients with paracoccidioidomycosis, the migration of Treg cells is dependent on the axis chemokine-chemokine receptors, and CCR5 ligands are produced in P. brasiliensis-induced lesions, we investigated the role of CCR5 in the control of the infection. The results showed that CCR5(-/-) mice are more efficient in controlling fungal growth and dissemination and exhibited smaller granulomas than wild-type (WT) mice. In the absence of CCR5, the percentage of CD4(+)CD25(+) T cells expressing Foxp3, glucocorticoid-induced TNFR (GITR), CD103, CD45(low), and CTLA-4 in the granulomas was significantly decreased. Interestingly, P. brasiliensis infection resulted in an absence of T cell proliferation in response to Con A in WT but not CCR5(-/-) mice that was abrogated by anti-CTLA-4 mAb and anti-GITR mAb. Moreover, the adoptive transfer of CD4(+)CD25(+) but not CD4(+)CD25(-) T cells from infected WT to infected CCR5(-/-) mice resulted in a significant increase in fungal load. Overall, CCR5 is a key receptor for the migration of Treg cells to the site of P. brasiliensis infections leading to down-modulation of effector immune response and the long-term presence of the fungus in the granulomas. Thus, a tight control of Treg cell migration to the granulomatous lesions could be an important mechanism for avoiding exacerbation and reactivation of the disease.