表达CCR4的树突状细胞和调节性T细胞可抵抗柯萨奇病毒B5诱导的胰腺炎。,Scientific Reports

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表达CCR4的树突状细胞和调节性T细胞可抵抗柯萨奇病毒B5诱导的胰腺炎。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-10-14 , DOI: 10.1038/s41598-019-51311-9
Marcela C S Françozo ₁ , Frederico R C Costa ₂ , Isabel C Guerra-Gomes ₂ , João S Silva _{2,

3} , Renata Sesti-Costa ₄

Affiliation

B型柯萨奇病毒（CVB）是负责普通传染性心肌炎和胰腺炎的肠病毒。DC和调节性T细胞（Tregs）是分别控制病毒复制和调节免疫应答和组织损伤的关键因素。但是，细胞向靶组织迁移的机制尚不清楚。在本研究中，我们发现CVB5感染诱导了CCL17的产生并控制了CCR4 + DC和CCR4 + Treg向胰腺淋巴结（pLN）的迁移。CCR4-/-小鼠的CVB5感染减少了CD8α+ DC亚群的迁移，并减少了DC激活以及IFN-β和IL-12的产生。因此，CCR4-/-小鼠表现出减少的产生IFN-γ的CD4 +和CD8 + T细胞，病毒载量增加和更严重的胰腺炎。此外，CCR4-/-小鼠在pLN中的Treg蓄积受损，并且T淋巴细胞活化增加。CCR4 + Treg的过继转移而不是CCR4- Treg的过继转移能够调节CVB5感染后的T淋巴细胞活化。本数据揭示了CCR4在协调免疫细胞向CVB感染组织的迁移以及控制随后的胰腺炎中的未知作用。这些新见解可能有助于设计未来用于非脊髓灰质炎性肠病毒急性和慢性感染的治疗方法。

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Dendritic cells and regulatory T cells expressing CCR4 provide resistance to coxsackievirus B5-induced pancreatitis.

Type B coxsackieviruses (CVB) are enteroviruses responsible for a common infectious myocarditis and pancreatitis. DCs and regulatory T cells (Tregs) are key players in controlling virus replication and regulating the immune response and tissue damage, respectively. However, the mechanisms underlying cellular migration to target tissues remain unclear. In the present study, we found that CVB5 infection induced CCL17 production and controlled the migration of CCR4+ DCs and CCR4+ Tregs to the pancreatic lymph nodes (pLN). CVB5 infection of CCR4-/- mice reduced the migration of the CD8α+ DC subset and reduced DC activation and production of IFN-β and IL-12. Consequently, CCR4-/- mice presented decreased IFN-γ-producing CD4+ and CD8+ T cells, an increased viral load and more severe pancreatitis. In addition, CCR4-/- mice had impaired Treg accumulation in pLN as well as increased T lymphocyte activation. Adoptive transfer of CCR4+ Tregs but not CCR4- Tregs was able to regulate T lymphocyte activation upon CVB5 infection. The present data reveal a previously unknown role for CCR4 in coordinating immune cell migration to CVB-infected tissues and in controlling subsequent pancreatitis. These new insights may contribute to the design of future therapies for acute and chronic infection of non-polio enteroviruses.

更新日期：2019-10-14

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