IL-15 Amplifies the Pathogenic Properties of CD4+CD28- T Cells in Multiple Sclerosis
IL-15 Amplifies the Pathogenic Properties of CD4+CD28- T Cells in Multiple Sclerosis
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DOI：
10.4049/jimmunol.1401547
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发表时间：
2015-03-01
影响因子：
4.4
通讯作者：
Hellings, Niels
中科院分区：
文献类型：
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作者：
Broux, Bieke;Mizee, Mark R.;Hellings, Niels
CD4(+)CD28(-) T细胞通过反复的抗原刺激产生，存在于各种自身免疫性疾病（包括多发性硬化症（MS））患者的病变组织中。这些细胞被认为具有细胞毒性，可导致靶器官的致病性损伤。病变组织中增加的内源性信号可能会增强CD4(+)CD28(-) T细胞的活性。在这项研究中，我们关注的是IL-15，一种在MS患者血清和脑脊液中增加的促进细胞毒性的细胞因子。通过免疫组化，我们发现IL-15主要由MS患者炎性病变中的星形胶质细胞和浸润性巨噬细胞产生。此外，体外转运研究表明，IL-15选择性地吸引MS患者的CD4(+)CD28(-) T细胞，而不是健康个体。流式细胞术研究表明，IL-15进一步诱导趋化因子受体和黏附分子在CD4(+)CD28(-) T细胞上的表达，导致在单层人脑内皮细胞上的迁移增强。最后，流式细胞术分析显示，IL-15增加了GM-CSF的增殖和产生，细胞毒性分子（NKG2D、穿孔素和颗粒酶B）的表达，以及CD4(+)CD28(-) T细胞的脱粒能力。综上所述，这些发现表明，外周血和局部IL-15水平的升高会增强CD4(+)CD28(-) T细胞的致病潜力，从而导致MS脑病变中的组织损伤。
CD4(+)CD28(-) T cells arise through repeated antigenic stimulation and are present in diseased tissues of patients with various autoimmune disorders, including multiple sclerosis (MS). These cells are believed to have cytotoxic properties that contribute to the pathogenic damaging of the target organ. Endogenous cues that are increased in the diseased tissue may amplify the activity of CD4(+)CD28(-) T cells. In this study, we focused on IL-15, a cytotoxicity-promoting cytokine that is increased in the serum and cerebrospinal fluid of MS patients. Using immunohistochemistry, we demonstrate that IL-15 is mainly produced by astrocytes and infiltrating macrophages in inflammatory lesions of MS patients. Moreover, in vitro transmigration studies reveal that IL-15 selectively attracts CD4(+)CD28(-) T cells of MS patients, but not of healthy individuals. IL-15 further induces the expression of chemokine receptors and adhesionmolecules on CD4(+)CD28(-) T cells, as investigated using flow cytometry, resulting in enhanced migration over a monolayer of human brain endothelial cells. Finally, flow cytometric analyses revealed that IL-15 increases the proliferation and production of GM-CSF, expression of cytotoxic molecules (NKG2D, perforin, and granzyme B), and degranulation capacity of CD4(+)CD28(-) T cells. Taken together, these findings indicate that increased peripheral and local levels of IL-15 amplify the pathogenic potential of CD4(+)CD28(-) T cells, thus contributing to tissue damage in MS brain lesions.