Galectin-3藉由誘發調控性T細胞於小鼠模式中減緩腸道發炎性疾病

Abstract

Galectin-3是半乳糖苷結合凝集素的一種，具有廣泛的生物功能，參與在細胞的附著、活化、生長調控和凋亡。我們發現galectin-3可以引發T細胞表現FOXP3，這群由galectin-3所引起的FOXP3+ T細胞具有抑制性功能，能夠在共同培養的情形下抑制responder T細胞的活化增殖。另外，galectin-3在dextran sulfate sodium (DSS) 所引起的inflammatory bowel disease (IBD) 小鼠模式中也表現了其抑制性質，可以有效降低腸道發炎的症狀。我們以腹腔注射方法給予小鼠galectin-3，可以成功改善小鼠的腸道炎發病程度，而若是在galectin-3-/-小鼠上利用相同方式引發IBD，其發炎病狀會比野生型小鼠更加嚴重，這顯示了內生性galectin-3在腸道發炎反應的調控上也扮演著重要角色。接下來，我們進一步探討galectin-3的作用機制，藉由移植CD4+CD25- T細胞到免疫缺失小鼠體內以引發IBD的動物模式，我們發現經過galectin-3處理的CD4+CD25- T 細胞較不容易引起腸道炎，實驗結果顯示galectin-3可以作用在T細胞上，並且能調節CD4+CD25- T 細胞促進發炎的性質。另一方面，我們也利用施打anti-CD25單株抗體的方式去拮抗小鼠體內的調控性T細胞，以研究調控性Ｔ細胞是否參與在galectin-3的抑制性功能中。我們發現，一旦調控性T細胞被拮抗，galectin-3在DSS所引起的IBD小鼠模式裡就無法具有抑制發炎的效果，因此galectin-3的抑制性功能必須透過regulatory T 細胞才能發揮作用。以上實驗結果顯示著galectin-3能夠引發一群具有抑制性功能的FOXP3+ T細胞，從而調控腸道發炎反應。

Galectin-3, a member of the β-galectoside-binding lectin family, exerts broad biological functions, involving in cell adhesion, cell activation, cell growth and apoptosis. We demonstrated that galectin-3 could induce FOXP3 expression in T cells and those FOXP3+ T cells induced by galectin-3 could supress T cell proliferation in vitro. In addition, galectin-3 could reduce inflammation in dextran sulfate sodium (DSS)–induced inflammatory bowel disease (IBD) mouse model. Treatment with soluble galectin-3 was able to ameliorate the severity of colitis in mice. On the other hand, galectin-3-/- mice demonstrated more severe inflammation in IBD model compared with wild type mice, suggesting that endogenous galectin-3 played an important role in regulation of intestinal inflammation. Moreover, we addressed the mechanism underlying the suppressive function of galectin-3 in vivo using another IBD mouse model which is induced by adoptive transfer with CD4+CD25- T cells into immunodeficient mice. Our results further demonstrated that galectin-3 could interact with T cells and reduce the severity of colitis induced by CD4+CD25- T cells. Furthermore, using anti-CD25 mAb to deplete Treg cells in vivo, we also found that the suppressive function of galectin-3 was mediated by regulatory T cells. In conclusion, these findings indicate that galectin-3 induces a population of FOXP3+ T cells with suppressive activity and involves in regulation of intestinal inflammation.