Galazka Grazyna, Jurewicz Anna, Orlowski Wojciech, Stasiolek Mariusz, Brosnan Celia F, Raine Cedric S, Selmaj Krzysztof
Department of Neurology, Medical University of Lodz, Lodz, Poland.
J Immunol. 2007 Oct 1;179(7):4503-12. doi: 10.4049/jimmunol.179.7.4503.
Inflammation leads to induction of tissue stress conditions that might contribute to the generation of mechanisms limiting ongoing immune responses. We have shown previously that peptides derived from brain tissue of mice with experimental autoimmune encephalomyelitis (EAE) complexed with the chaperone heat shock protein 70 (Hsp70-pc) induce an NK-cell-dependent tolerance for subsequent EAE sensitization. We now present data that showed that the MHC class I-related glycoprotein H60 determines Hsp70-pc-induced EAE inhibition. Hsp70-pc led to significant and selective up-regulation of H60 expression in SJL/J mice, and Ab-blocking of H60 expression led to loss of EAE tolerance. Similarly, blocking of the NK cell receptor for H60, NKG2D, also reversed the Hsp70-pc-induced EAE inhibition. In contrast, in C57BL/6 mice H60 was not expressed, and Hsp70-pc-induced tolerance was not detected. The NK cell mediated Hsp70-pc-induced tolerance to EAE was dependent on modulation of dendritic cells function leading to diminished T cell reactivity to PLP. As, no increase of H60 expression on T cells from EAE mice immunized with PLP was detected, and no enhanced loss of CD3+ H60+ over CD3+ H60- cells in Hsp70-pc-induced EAE tolerance was found direct killing of H60+ PLP-reactive cells seems not to be involved in the Hsp70-pc-induced tolerance induction. We have provided evidence that Hsp70-pc-induced tolerance for EAE, mediated by NK cells, involves induction of H60 ligand and its interaction with NKG2D receptor. NK cells tolerization of EAE depends on altered dendritic cells activity leading to enhanced death of Ag reactive cells.
炎症会引发组织应激状态，这可能有助于产生限制持续免疫反应的机制。我们之前已经表明，从患有实验性自身免疫性脑脊髓炎（EAE）的小鼠脑组织中提取的肽与伴侣热休克蛋白70复合（Hsp70-pc），可诱导对随后EAE致敏的NK细胞依赖性耐受。我们现在展示的数据表明，MHC I类相关糖蛋白H60决定了Hsp70-pc诱导的EAE抑制作用。Hsp70-pc导致SJL/J小鼠中H60表达显著且选择性上调，而对H60表达的抗体阻断导致EAE耐受性丧失。同样，阻断H60的NK细胞受体NKG2D也会逆转Hsp70-pc诱导的EAE抑制作用。相比之下，在C57BL/6小鼠中未检测到H60表达，也未检测到Hsp70-pc诱导的耐受性。NK细胞介导的Hsp70-pc诱导的EAE耐受性取决于树突状细胞功能的调节，导致T细胞对PLP的反应性降低。由于在用PLP免疫的EAE小鼠的T细胞上未检测到H60表达增加，并且在Hsp70-pc诱导的EAE耐受性中未发现CD3 + H60 +细胞相对于CD3 + H60 -细胞的增强丢失，因此H60 + PLP反应性细胞的直接杀伤似乎不参与Hsp70-pc诱导的耐受性诱导。我们已经提供证据表明，由NK细胞介导的Hsp70-pc诱导的EAE耐受性涉及H60配体的诱导及其与NKG2D受体的相互作用。NK细胞对EAE的耐受性取决于树突状细胞活性的改变，导致Ag反应性细胞的死亡增加。
