FTY720 suppresses CD4+CD44highCD62L- effector memory T cell-mediated colitis
FTY720 suppresses CD4+CD44highCD62L- effector memory T cell-mediated colitis
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DOI：
10.1152/ajpgi.00496.2005
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发表时间：
2006-08-01
影响因子：
4.5
通讯作者：
Watanabe, M.
中科院分区：
文献类型：
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作者：
Fujii, R.;Kanai, T.;Watanabe, M.
FTY720是一种鞘氨醇衍生的免疫调节剂，通过加强淋巴细胞对次级淋巴器官的隔离作用而导致免疫抑制，从而防止其抗原激活的T细胞向炎症部位外流。FTY720对多种动物模型的自身免疫抑制作用显著。然而，FTY720如何控制记忆T细胞的迁移特性却鲜为人知。在这里，我们证明了FTY720防止由过继转移固有层(LP)结肠炎效应记忆CD4(+)T细胞(T-EM细胞；CD45RB(低)CD44(高)CD62L(-))到严重联合免疫缺陷(SCID)小鼠而导致的结肠炎的发展，并抑制LP CD4(+)T细胞产生干扰素-γ、白介素2和肿瘤坏死因子-α。FTY720组小鼠的脾、外周血、肠系膜淋巴结和Lp CD4(+)T细胞数均显著低于对照组。值得注意的是，LP CD4(+)T-EM细胞以及脾CD4(+)CD45RB(高)T细胞表达几种作为FTY720靶标的Spingosine-1-磷酸受体。此外，FTY720还可预防过继转移脾CD4(+)CD45RB(High)T细胞至SCID小鼠所致的结肠炎的发生。总而言之，目前的数据表明，FTY720治疗不仅有可能预防疾病的发生，还可能治疗记忆T细胞介导的自身免疫性疾病，包括炎症性肠病。
FTY720, a sphingosine-derived immunomodulator, causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, thereby preventing their antigen-activated T cell egress to sites of inflammation. FTY720 is highly effective in inhibiting autoimmunity in various animal models. However, there is little known about how FTY720 controls the migration property of memory T cells. Here, we demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of lamina propria (LP) colitogenic effector memory CD4(+) T cells (T-EM cells; CD45RB(low)CD44(high)CD62L(-)) into severe combined immunodeficiency (SCID) mice and suppresses interferon-gamma, interleukin-2, and tumor necrosis factor-alpha production by LP CD4(+) T cells. The numbers of spleen, peripheral blood, mesenteric lymph node, and LP CD4(+) T cells in FTY720-treated mice were significantly reduced compared with those in control mice. Notably, LP CD4(+) T-EM cells as well as splenic CD4(+)CD45RB(high) T cells expressed several spingosine-1-phosphate receptors that are targets for FTY720. Furthermore, FTY720 also prevented the development of colitis induced by the adoptive transfer of splenic CD4(+)CD45RB(high) T cells into SCID mice. Collectively, the present data indicate that FTY720 treatment may offer the potential not only to prevent the onset of disease but also to treat memory T cell-mediated autoimmune diseases including inflammatory bowel diseases.