Bordetella Adenylate Cyclase Toxin Differentially Modulates Toll-Like Receptor-Stimulated Activation, Migration and T Cell Stimulatory Capacity of Dendritic Cells
Bordetella Adenylate Cyclase Toxin Differentially Modulates Toll-Like Receptor-Stimulated Activation, Migration and T Cell Stimulatory Capacity of Dendritic Cells
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DOI：
10.1371/journal.pone.0104064
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发表时间：
2014-08-01
期刊：
影响因子：
3.7
通讯作者：
Sebo, Peter
中科院分区：
文献类型：
--
作者：
Adkins, Irena;Kamanova, Jana;Sebo, Peter
腺苷酸环化酶毒素（CyaA）是百日咳杆菌的关键毒力因子。这种毒素以表达cd11b的吞噬细胞为目标，并将腺苷酸环化酶（AC）酶传递到它们的细胞质中，这种酶通过增加cAMP水平来破坏细胞信号。在本研究中，我们分析了CyaA对toll样受体（TLR）激活的小鼠和人树突状细胞（dc）的粘附、迁移和抗原提呈特性的调节作用。CyaA的cAMP信号传导增强了tlr诱导的细胞粘附接触的溶解和dc向淋巴结归巢趋化因子CCL19和CCL21的迁移。此外，我们详细研究了毒素处理的dc诱导CD4（+）和CD8(+) T细胞反应的能力。暴露于CyaA降低了lps刺激的dc向CD4(+) T细胞呈递可溶性蛋白抗原的能力，而不依赖于共刺激分子的调节和细胞因子的产生，并增强了它们在体外促进CD4(+) CD25(+) Foxp3(+) T调节细胞的能力。此外，CyaA降低了lps刺激的dc诱导CD8(+) T细胞增殖的能力，限制了诱导产生ifn - γ的CD8(+) T细胞的能力，同时增强了IL-10和il -17的产生。这些结果表明，通过激活cAMP信号，CyaA可能动员T细胞刺激能力受损的dc，并且这些dc到达引流淋巴结可能有助于延迟和颠覆百日咳感染期间宿主免疫反应。
Adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. The toxin targets CD11b-expressing phagocytes and delivers into their cytosol an adenylyl cyclase (AC) enzyme that subverts cellular signaling by increasing cAMP levels. In the present study, we analyzed the modulatory effects of CyaA on adhesive, migratory and antigen presenting properties of Toll-like receptor (TLR)-activated murine and human dendritic cells (DCs). cAMP signaling of CyaA enhanced TLR-induced dissolution of cell adhesive contacts and migration of DCs towards the lymph node-homing chemokines CCL19 and CCL21 in vitro. Moreover, we examined in detail the capacity of toxin-treated DCs to induce CD4(+) and CD8(+) T cell responses. Exposure to CyaA decreased the capacity of LPS-stimulated DCs to present soluble protein antigen to CD4(+) T cells independently of modulation of co-stimulatory molecules and cytokine production, and enhanced their capacity to promote CD4(+) CD25(+) Foxp3(+) T regulatory cells in vitro. In addition, CyaA decreased the capacity of LPS-stimulated DCs to induce CD8(+) T cell proliferation and limited the induction of IFN-gamma producing CD8(+) T cells while enhancing IL-10 and IL-17-production. These results indicate that through activation of cAMP signaling, the CyaA may be mobilizing DCs impaired in T cell stimulatory capacity and arrival of such DCs into draining lymph nodes may than contribute to delay and subversion of host immune responses during B. pertussis infection.