Rojo Jose M, Pini Eliana, Ojeda Gloria, Bello Raquel, Dong Chen, Flavell Richard A, Dianzani Umberto, Portolés Pilar
Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, E-28040 Madrid, Spain.
Int Immunol. 2008 Apr;20(4):577-89. doi: 10.1093/intimm/dxn016. Epub 2008 Feb 28.
The inducible co-stimulator (ICOS, CD278) is essential to the efficient development of normal and pathological immune reactions. Since ICOS-deficient mice have enhanced susceptibility to experimental allergic encephalomyelitis (EAE), we have functionally analyzed a CD4+ICOS+ population comprising 6-15% of all CD4+ T cells in secondary lymphoid organs of unmanipulated wild-type mice and checked for their ability to suppress EAE. In C57BL/6 mice, CD4+ICOS+ cells were a major source of cytokines including IFN-gamma, IL-2, IL-4, IL-10 or IL-17A. Upon activation, these cells showed preferentially enhanced production of IL-4 or IL-10 but inhibited IFN-gamma production. In contrast, CD4+ICOS- cells mainly produced IFN-gamma. Interestingly, CD4+ICOS+ cells partially suppressed the proliferation of CD4+ICOS- or CD4+CD25- lymphocytes 'in vitro' by an IL-10-dependent mechanism. Furthermore, CD4+ICOS+ activated and expanded under appropriate conditions yielded a population enriched in cells producing IL-10 and T(h)2 cytokines that also suppressed the proliferation of CD4+CD25- lymphocytes. CD4+ICOS+ cells, before or after expansion in vitro, reduced the severity of EAE when transferred to ICOS-deficient mice. In the same EAE model, lymph node cells from ICOS-deficient mice receiving ICOS+ cells showed reduced IL-17A production and enhanced IL-10 secretion upon antigen activation in vitro. Thus, naturally occurring CD4+ICOS+ cells, expanded or not in vitro, are functionally relevant cells able of protecting ICOS-deficient mice from severe EAE.
诱导性共刺激分子（ICOS，CD278）对于正常和病理性免疫反应的有效发展至关重要。由于ICOS缺陷小鼠对实验性自身免疫性脑脊髓炎（EAE）的易感性增强，我们对未处理的野生型小鼠二级淋巴器官中占所有CD4⁺ T细胞6% - 15%的CD4⁺ICOS⁺细胞群进行了功能分析，并检测了它们抑制EAE的能力。在C57BL/6小鼠中，CD4⁺ICOS⁺细胞是包括干扰素-γ、白细胞介素-2、白细胞介素-4、白细胞介素-10或白细胞介素-17A在内的细胞因子的主要来源。激活后，这些细胞优先增强白细胞介素-4或白细胞介素-10的产生，但抑制干扰素-γ的产生。相比之下，CD4⁺ICOS⁻细胞主要产生干扰素-γ。有趣的是，CD4⁺ICOS⁺细胞通过依赖白细胞介素-10的机制在“体外”部分抑制CD4⁺ICOS⁻或CD4⁺CD25⁻淋巴细胞的增殖。此外，在适当条件下激活并扩增的CD4⁺ICOS⁺细胞产生了富含产生白细胞介素-10和辅助性T细胞2型（Th2）细胞因子的细胞群，该细胞群也抑制了CD4⁺CD25⁻淋巴细胞的增殖。体外扩增前后的CD4⁺ICOS⁺细胞转移到ICOS缺陷小鼠后，可减轻EAE的严重程度。在同一EAE模型中，接受ICOS⁺细胞的ICOS缺陷小鼠的淋巴结细胞在体外抗原激活后，白细胞介素-17A的产生减少，白细胞介素-10的分泌增加。因此，无论是否在体外扩增，天然存在的CD4⁺ICOS⁺细胞都是能够保护ICOS缺陷小鼠免受严重EAE侵害的功能相关细胞。
