B220+ DN alphabeta T cell as a novel immunoregulatory T*

描述（由申请人提供）：自身反应性CD4和CD8 T细胞和大量B220+ CD4-CD8双阴性（DN） T细胞在fas介导的细胞凋亡受损的小鼠中积累，导致自身免疫淋巴细胞增殖。类似的自身免疫性疾病（ALPS）也发生在Fas通路受损的人身上。矛盾的是，与Fas通路功能丧失相关的T细胞淋巴增生不会导致T细胞介导的显性自身免疫。Fas通路的损伤甚至赋予小鼠对自身免疫性糖尿病的抵抗力。无论是B220+ DN T细胞的功能，还是受影响的自身反应性T细胞的控制机制都不清楚。我们研究并发现B220+ DN T细胞是免疫调节性T细胞，在体外抑制多克隆和抗原特异性T细胞活化，并在炎症性肠病动物模型中预防T细胞介导的结肠炎。在正常动物中，B220+ DN T细胞存在于阑尾和大肠中。我们假设B220+ DN T细胞对维持粘膜和外周耐受性很重要。我们提出了两个具体的目标来研究这一假设：1)为了了解B220+ DN T细胞介导的抑制的分子机制，我们将使用DNA微阵列分析和体外和体内功能研究来鉴定其产物参与介导B220+ DN T细胞抑制功能的基因。2)为了明确B220+ DN T细胞在全身和粘膜耐受中的作用，我们将分析新生儿移植B220+ DN T细胞是否会阻止a)安全小鼠的致死性淋巴细胞增殖或b) IL-10缺陷小鼠的小肠结肠炎。这些研究结果将有助于表征一种新的自然发生的调节性T细胞，并确定它们在外周和粘膜耐受中的作用。

DESCRIPTION (provided by applicant): Autoreactive CD4 and CD8 T cells and large numbers of B220+ CD4-CD8-double negative (DN) (( T cells accumulate in mice with impaired Fas-mediated apoptosis leading to autoimmune lymphoproliferation. Similar autoimmune disease (ALPS) occurs in humans with impaired Fas pathway. Paradoxically, T cell lymphoproliferation associated with loss of function in the Fas pathway does not result in overt T cell-mediated autoimmunity. Impairment of the Fas pathway even confers resistance to autoimmune diabetes in mice. Neither the function of B220+ DN T cells, nor the mechanism by which the autoreactive T cells in affected are controlled is clearly understood. We have examined and found that B220+ DN T cells are immunoregulatory T cells that suppress polyclonal and antigen specific T cell activation in vitro and prevent T cell-mediated colitis in an animal model of inflammatory bowel disease. In normal animals, B220+ DN T cells are found in the appendix and large intestine. We hypothesize that B220+ DN T cells are important for maintenance of mucosal and peripheral tolerance. We propose two specific aims to investigate this hypothesis: 1) To understanding the molecular mechanism of B220+ DN T cell-mediated suppression, we will use DNA microarray assay and in vitro and in vivo functional studies to identify genes whose products are involved in mediating B220+ DN T cell suppressor function. 2) To define the role of B220+ DN T cells in systemic and mucosal tolerance, we will analyze whether neonatal transfer of B220+ DN T cells prevents a) the fatal lymphoproliferation in scurfy mice or b) enterocolitis in IL-10 deficient mice. The findings generated by these studies will aid in characterizing a novel naturally occurring regulatory T cells and define their role in peripheral and mucosal tolerance.