A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens.
A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens.
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DOI：
10.1073/pnas.94.17.9279
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发表时间：
1997-08
影响因子：
11.1
通讯作者：
Lindsay B. Nicholson;Anwar Murtaza;B. Hafler;Alessandro Sette;Vijay K. Kuchroo
中科院分区：
文献类型：
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作者：
Lindsay B. Nicholson;Anwar Murtaza;B. Hafler;Alessandro Sette;Vijay K. Kuchroo
用髓磷脂蛋白脂质蛋白（PLP）残基139-151（HSLGKWLGHPDKF）诱导的实验性自身免疫性脑脊髓炎（EAE）可以通过用T细胞受体（TCR）拮抗剂肽（L144/R147）治疗来预防，所述T细胞受体拮抗剂肽通过取代致脑炎肽中的两个主要TCR接触残基而产生。TCR拮抗肽在体外阻断致脑炎性Th 1辅助细胞的活化，但拮抗肽在体内阻断EAE的机制尚不清楚。用L144/R147免疫不抑制体内PLP-（139-151）特异性T细胞的产生。此外，用L144/R147预免疫保护小鼠免受由致脑炎肽PLP-（178-191）和髓鞘少突胶质细胞蛋白（MOG）残基92-106以及小鼠髓鞘碱性蛋白（MBP）诱导的EAE。这些数据表明，L144/R147肽在体内不作为拮抗剂，但介导旁观者抑制，可能是通过产生调节性T细胞。为了证实这一点，我们从用PLP-（139-151）加L144/R147免疫的动物产生T细胞系和克隆。对L144/R147肽特异的T细胞与天然PLP-（139-151）肽交叉反应，产生Th 2/Th 0细胞因子，并在过继转移后抑制EAE。这些研究表明，TCR拮抗剂肽在体内可能具有多种生物学效应。这些肽抑制自身免疫的主要机制之一是通过诱导调节性T细胞，导致EAE的旁观者抑制。这些结果对于治疗自身免疫性疾病具有重要意义，其中靶器官中存在对多种抗原的自体致病反应。
Experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) residues 139-151 (HSLGKWLGHPDKF) can be prevented by treatment with a T cell receptor (TCR) antagonist peptide (L144/R147) generated by substituting at the two principal TCR contact residues in the encephalitogenic peptide. The TCR antagonist peptide blocks activation of encephalitogenic Th1 helper cells in vitro, but the mechanisms by which the antagonist peptide blocks EAE in vivo are not clear. Immunization with L144/R147 did not inhibit generation of PLP-(139-151)-specific T cells in vivo. Furthermore, preimmunization with L144/R147 protected mice from EAE induced with the encephalitogenic peptides PLP-(178-191) and myelin oligodendrocyte protein (MOG) residues 92-106 and with mouse myelin basic protein (MBP). These data suggest that the L144/R147 peptide does not act as an antagonist in vivo but mediates bystander suppression, probably by the generation of regulatory T cells. To confirm this we generated T cell lines and clones from animals immunized with PLP-(139-151) plus L144/R147. T cells specific for L144/R147 peptide were crossreactive with the native PLP-(139-151) peptide, produced Th2/Th0 cytokines, and suppressed EAE upon adoptive transfer. These studies demonstrate that TCR antagonist peptides may have multiple biological effects in vivo. One of the principal mechanisms by which these peptides inhibit autoimmunity is by the induction of regulatory T cells, leading to bystander suppression of EAE. These results have important implications for the treatment of autoimmune diseases where there are autopathogenic responses to multiple antigens in the target organ.