Division of Infectious Diseases, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Infect Immun. 2010 May;78(5):2125-37. doi: 10.1128/IAI.00065-10. Epub 2010 Mar 1.
Excessive production of interleukin-4 impairs clearance of the fungal pathogen Histoplasma capsulatum in mice lacking the chemokine receptor CCR2. An increase in the interleukin-4 level is associated with decreased recruitment of dendritic cells to lungs; therefore, we investigated the possibility that these cells influence interleukin-4 production. Adoptive transfer of wild-type or CCR2(-/-) bone marrow-derived dendritic cells loaded with heat-killed yeast cells to infected CCR2(-/-) mice suppressed interleukin-4 transcription. Surprisingly, transfer of cells did not reduce the fungal burden despite the fact that it limited interleukin-4 transcription. Yeast cell-loaded bone marrow-derived dendritic cell-mediated regulation of interleukin-4 transcription was dependent on major histocompatibility complex II antigen presentation to CD4(+) T cells. We previously showed that CD4(+) T cells were a source of interleukin-4 in infected CCR2(-/-) mice, but their contribution to the TH2 phenotype was unclear. Here we demonstrated that these cells were functionally important since elimination of them prior to infection, but not elimination of them at the time of infection, reduced the interleukin-4 level in infected CCR2(-/-) mice. However, the fungal burden was reduced only in CD4-depleted CCR2(-/-) mice that received yeast cell-loaded bone marrow-derived dendritic cells. Taken together, the data indicate that generation of excess interleukin-4 in lungs of H. capsulatum-infected CCR2(-/-) mice is at least partially a consequence of decreased recruitment of dendritic cells capable of antigen presentation. Furthermore, CD4(+) T cells had a deleterious impact on immunity in infected CCR2(-/-) mice.
白细胞介素-4 过度产生会损害缺乏趋化因子受体 CCR2 的小鼠对真菌病原体荚膜组织胞浆菌的清除。白细胞介素-4 水平的增加与树突状细胞向肺部的募集减少有关；因此，我们研究了这些细胞是否会影响白细胞介素-4 的产生。将负载热灭活酵母细胞的野生型或 CCR2(-/-)骨髓来源的树突状细胞过继转移到感染的 CCR2(-/-)小鼠中，抑制了白细胞介素-4 的转录。令人惊讶的是，尽管细胞转移限制了白细胞介素-4 的转录，但它并没有降低真菌负荷。酵母细胞负载的骨髓来源的树突状细胞介导的白细胞介素-4 转录调节依赖于主要组织相容性复合物 II 抗原呈递给 CD4(+)T 细胞。我们之前表明，CD4(+)T 细胞是感染的 CCR2(-/-)小鼠中白细胞介素-4 的来源，但它们对 TH2 表型的贡献尚不清楚。在这里，我们证明了这些细胞是功能上重要的，因为在感染前消除它们，但不在感染时消除它们，会降低感染的 CCR2(-/-)小鼠中的白细胞介素-4 水平。然而，只有在感染前耗尽 CD4 的 CCR2(-/-)小鼠中，接受负载酵母细胞的骨髓来源的树突状细胞后，真菌负荷才会降低。总之，这些数据表明，荚膜组织胞浆菌感染的 CCR2(-/-)小鼠肺部产生过多的白细胞介素-4，至少部分是由于能够呈递抗原的树突状细胞募集减少的结果。此外，CD4(+)T 细胞对感染的 CCR2(-/-)小鼠的免疫产生了有害影响。
