Low CD86 expression in the nonobese diabetic mouse results in the impairment of both T cell activation and CTLA-4 up-regulation
Low CD86 expression in the nonobese diabetic mouse results in the impairment of both T cell activation and CTLA-4 up-regulation
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DOI：
10.4049/jimmunol.164.5.2444
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发表时间：
2000-03-01
影响因子：
4.4
通讯作者：
Dawe, K
中科院分区：
文献类型：
--
作者：
Dahlén, E;Hedlund, G;Dawe, K
非肥胖糖尿病（NOD）小鼠自发发展自身免疫性胰岛素依赖型糖尿病，并作为人类I型糖尿病的模型。NOD脾细胞对抗CD 3抗体的反应比C57 BL/6和BALB/c小鼠的脾细胞增殖程度低。为了研究这种降低的T细胞增殖的原因，研究了共刺激分子表达。发现与C57 BL/6和BALB/c相比，NOD巨噬细胞、树突状细胞和T细胞表达较低水平的CD 86，但不表达CD 80、CD 28或CD 40，而不表达B/c。这种低CD 86表达不依赖于MHC单倍型或糖尿病发展，因为NOD相关的无糖尿病小鼠品系NON（H-2（nb 1））和NOR（H-2（g7））表现出相似的低水平CD 86表达和增殖。此外，活化后，与CD 28相比，CTLA-4的相对上调在C57 BL/6和BALB/c T细胞上更明显，如CTLA-4/CD 28比率增加所示。与其他两种菌株相比，这种活化诱导的CTLA-4/CD 28比率增加在NOD T细胞上显著降低。NOD小鼠中的低CD 86表达可以解释增殖和CTLA-4/CD 28比率的降低的增加，因为将C57 BL/6和BALB/c培养物中的CD 86表达降低至NOD水平显著降低了增殖和CTLA-4/CD 28比率。因此，我认为NOD小鼠中低水平的CD 86表达通过阻止T细胞的完全活化以及CTLA-4的上调而导致自身反应性T细胞的调节缺陷。
The nonobese diabetic (NOD) mouse spontaneously develops autoimmune insulin-dependent diabetes mellitus and serves as a model for human type I diabetes. NOD spleen cells proliferate to a lesser extent than those from C57BL/6 and BALB/c mice in response to anti-CD3. To investigate the cause of this reduced T cell proliferation, costimulatory molecule expression was investigated, It was found that NOD macrophages, dendritic cells, and T cells, but not B cells, expressed lower basal levels of CD86, but not CD80, CD28, or CD40, compared with C57BL/6 and BALB/c. This low CD86 expression was not dependent on the MHC haplotype or on diabetes development since the NOD-related, diabetes-free mouse strains NON (H-2(nb1)) and NOR (H-2(g7)) exhibited similar low levels of CD86 expression and proliferation. Furthermore, following activation, the relative up-regulation of CTLA-4, as compared with CD28, was more pronounced on C57BL/6 and BALB/c T cells as shown by an increased CTLA-4/CD28 ratio. This activation-induced increase in the CTLA-4/CD28 ratio was markedly reduced on NOD T cells compared with the other two strains. The low CD86 expression in NOD mice may account for the reduced increase in both proliferation and the CTLA-4/CD28 ratio, since reducing CD86 expression in C57BL/6 and BALB/c cultures to NOD levels significantly reduces the proliferation and the CTLA-4/CD28 ratio. Therefore, me propose that a low level of CD86 expression in the NOD mouse contributes to a defective regulation of autoreactive T cells by preventing the full activation of T cells and therefore the up-regulation of CTLA-4.