Critical requirement of CD11b (Mac-1) on T cells and accessory cells for development of experimental autoimmune encephalomyelitis
Critical requirement of CD11b (Mac-1) on T cells and accessory cells for development of experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.175.10.6327
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发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Barnum, SR
中科院分区：
文献类型：
--
作者：
Bullard, DC;Hu, XZ;Barnum, SR
Mac-1（CD 18/CD 11b）是粘附分子β（2）-整联蛋白家族的成员，并且与许多炎性疾病的发展有关。Mac-1在CNS脱髓鞘疾病（包括多发性硬化症）发展中的作用尚不清楚，在多发性硬化症的动物模型实验性过敏性脑脊髓炎（EAE）中的Ab抑制研究产生了相互矛盾的结果。为了澄清这些结果，并确定Mac-1介导的机制在EAE，我们进行EAE使用Mac-1缺陷小鼠。Mac-1同源性缺陷，但不是Mac-1异源性缺陷小鼠，有显着延迟发病和衰减EAE。在疾病早期，两组小鼠的白细胞浸润相似，但在疾病晚期，受体缺陷小鼠的脊髓中白细胞浸润显著减少。将Ag-再刺激的T细胞从野生型连续转移到Mac-1缺陷型小鼠产生显著减弱的EAE，而将Mac-1缺陷型Ag-再刺激的T细胞转移到对照小鼠未能诱导EAE。来自髓鞘少突胶质细胞糖蛋白（MOG）（35-55）肽致敏Mac-1缺陷小鼠的T细胞显示出改变的细胞因子表型，与对照小鼠相比，TGF-β和IL-10水平升高，但IL-2、IFN-γ、TNF-α、IL-12和IL-4水平降低。在体外，经MOG（35-55）再刺激后，来自致敏小鼠的Mac-1缺陷型T细胞的增殖速度与对照T细胞的增殖速度一致。然而，在MOG（35-55）免疫后第10天，MAC-1缺陷型小鼠的引流淋巴结含有比对照小鼠低的原始T细胞频率，表明引发不良。我们的研究结果表明，Mac-1的表达是至关重要的吞噬细胞和T细胞的脱髓鞘疾病的发展。
Mac-1 (CD18/CD11b) is a member of the beta(2)-integrin family of adhesion molecules and is implicated in the development of many inflammatory diseases. The role of Mac-1 in the development of CNS demyelinating diseases, including multiple sclerosis, is not understood, and Ab inhibition studies in experimental allergic encephalomyelitis (EAE), the animal model for multiple sclerosis, have produced conflicting findings. To clarify these results and to determine Mac-1-mediated mechanisms in EAE, we performed EAE using Mac-1-deficient mice. Mac-1 homozygous-deficient, but not Mac-1 heterozygous-deficient mice, had significantly delayed onset and attenuated EAE. Leukocyte infiltration was similar in both groups of mice in early disease but significantly reduced in spinal cords of receptor-deficient mice in late disease. Adoptive transfer of Ag-restimulated T cells from wild-type to Mac-l-deficient mice produced significantly attenuated EAE, whereas transfer of Mac-1-deficient Ag-restimulated T cells to control mice failed to induce EAE. T cells from myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide-primed Mac-1-deficient mice displayed an altered cytokine phenotype with elevated levels of TGF-beta; and IL-10, but reduced levels of IL-2, IFN-gamma, TNF-alpha, IL-12, and IL-4 compared with control mice. Mac-1-deficient T cells from primed mice proliferated comparably to that of control T cells on MOG(35-55) restimulation in vitro. However, the draining lymph nodes of MAC-1-deficient mice on day 10 after MOG(35-55) immunization contained lower frequency of blast T cells than in control mice, suggesting poor priming. Our results indicate that Mac-1 expression is critical on both phagocytic cells and T cells for the development of demyelinating disease.