HLA-DQ6 (DQB1*0601)-restricted T cells protect against experimental autoimmune encephalomyelitis in HLA-DR3.DQ6 double-transgenic mice by generating anti-inflammatory IFN-γ
HLA-DQ6 (DQB1*0601)-restricted T cells protect against experimental autoimmune encephalomyelitis in HLA-DR3.DQ6 double-transgenic mice by generating anti-inflammatory IFN-γ
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DOI：
10.4049/jimmunol.180.11.7747
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
David, Chella
中科院分区：
文献类型：
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作者：
Mangalam, Ashutosh;Luckey, David;David, Chella
人类MHC II类基因与多发性硬化症（MS）的遗传易感性相关，多发性硬化症是一种推测为自身免疫起源的CNS慢性炎性脱髓鞘疾病。这些基因编码负责形成免疫反应的蛋白质。由于人类群体的高度多态性、连锁不平衡和异质性，HLA-DQ和-DR基因在疾病发病机制中的确切作用还不清楚。HLA II类转基因（Tg）小鼠的出现有助于回答这些问题。先前，使用单Tg小鼠（表达HLA-DR或-DQ基因），我们表明蛋白脂质蛋白（PLP）（91-110）肽仅在DR3.A β度小鼠中诱导经典的实验性自身免疫性脑脊髓炎，表明DR 3（DRB 1 *0301）是PLP背景下的疾病易感基因。人群研究表明，HLA-DQ 6（DQB 1 *0601）可能是一个保护性基因在MS。为了测试这种疾病的保护在实验模型中，我们产生了双Tg小鼠表达HLA-DR 3和-DQ 6。将DQ 6引入DR 3-Tg小鼠导致PLP 91 -110肽免疫后疾病发生率降低，表明DQ 6的显性保护作用。这种保护作用是由于DQ 6限制性T细胞产生的高水平IFN-γ，其通过诱导细胞凋亡抑制致脑炎性DR 3限制性T细胞的增殖。我们的研究表明，DQ 6通过IFN-γ的抗炎作用改变DR 3中PLP 91 -110特异性T细胞应答，这对实验性自身免疫性脑脊髓炎具有保护作用。因此，我们的双Tg小鼠提供了一种新的模型，其中研究MS中HLA 11类分子之间的上位相互作用。
The human MHC class II genes are associated with genetic susceptibility to multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS of presumed autoimmune origin. These genes encode for proteins responsible for shaping immune response. The exact role of HLA-DQ and -DR genes in disease pathogenesis is not well-understood due to the high polymorphism, linkage disequilibrium, and heterogeneity of human populations. The advent of HLA class II-transgenic (Tg) mice has helped in answering some of these questions. Previously, using single-Tg mice (expressing the HLA-DR or -DQ gene), we showed that proteolipid protein (PLP)(91-110) peptide induced classical experimental autoimmune encephalomyelitis only in DR3.A beta degrees mice, suggesting that DR3 (DRB1*0301) is a disease susceptible gene in the context of PLP. Human population studies have suggested that HLA-DQ6 (DQB1*0601) may be a protective gene in MS. To test this disease protection in an experimental model, we generated double-Tg mice expressing both HLA-DR3 and -DQ6. Introduction of DQ6 onto DR3-Tg mice led to a decrease in disease incidence on immunization with PLP91-110 peptide indicating a dominant protective role of DQ6. This protective effect is due to high levels of IFN-gamma produced by DQ6-restricted T cells, which suppressed proliferation of encephalitogenic DR3-restricted T cells by inducing apoptosis. Our study indicates that DQ6 modifies the PLP91-110-specific T cell response in DR3 through anti-inflammatory effects of IFN-gamma, which is protective for experimental autoimmune encephalomyelitis. Thus, our double-Tg mouse provides a novel model in which to study epistatic interactions between HLA class 11 molecules in MS.