Yashiro Takuya, Sakata Fumiya, Sekimoto Takahiro, Shirai Tomohiro, Hasebe Fumihito, Matsuda Kenichi, Kurosawa Sumire, Suzuki Shodai, Nagata Kazuki, Kasakura Kazumi, Nishiyama Makoto, Nishiyama Chiharu
a Department of Biological Science and Technology, Faculty of Industrial Science and Technology , Tokyo University of Science , Tokyo , Japan.
b Biotechnology Research Center, The University of Tokyo , Tokyo , Japan.
Biosci Biotechnol Biochem. 2019 Jun;83(6):1111-1116. doi: 10.1080/09168451.2019.1591262. Epub 2019 Mar 22.
The immunosuppressive activity of myriocin (ISP-1), a lead compound of fingolimod (FTY720), is derived from its 2-amino-1,3-propandiol structure. A non-proteinogenic amino acid, (2S,6R)-diamino-(5R,7)-dihydroxy-heptanoic acid (DADH), that contains this structure, was recently identified as a biosynthetic intermediate of a dipeptide secondary metabolite, vazabitide A, in Streptmyces sp. SANK 60404; however its effect on adaptive immunity has not yet been examined. In this study, we examined whether DADH suppresses mixed lymphocyte reaction using mouse bone marrow-derived dendritic cells (BMDCs) and allogeneic splenic T cells. Although T cell proliferation induced by cross-linking CD3 and CD28 were not suppressed by DADH unlike ISP-1, the pre-incubation of BMDCs with DADH but not ISP-1 significantly decreased allogeneic CD8 T cell expansion. Based on these results, we concluded that DADH suppresses DC-mediated T cell activation by targeting DCs.
米里霉素（ISP-1）是芬戈莫德（FTY720）的先导化合物，其免疫抑制活性源于其2-氨基-1,3-丙二醇结构。一种含有该结构的非蛋白质氨基酸，即(2S,6R)-二氨基-(5R,7)-二羟基庚酸（DADH），最近被鉴定为链霉菌属SANK 60404中二肽次级代谢产物瓦扎比特肽A的生物合成中间体；然而，其对适应性免疫的影响尚未得到研究。在本研究中，我们使用小鼠骨髓来源的树突状细胞（BMDCs）和同种异体脾T细胞，研究了DADH是否抑制混合淋巴细胞反应。尽管与ISP-1不同，DADH不会抑制由CD3和CD28交联诱导的T细胞增殖，但用DADH而非ISP-1预孵育BMDCs可显著降低同种异体CD8 T细胞的扩增。基于这些结果，我们得出结论，DADH通过靶向DCs抑制DC介导的T细胞活化。
