Development of strategy to treat allergic diseases via targeting surface molecules on lymphocytes and intracellular signaling molecules

T细胞免疫球蛋白粘蛋白(TIM)家族的成员控制着多种免疫反应，包括T细胞的Th1和Th2分化。我们发现TIM-3在C8树突状细胞(DC)上表达，并且TIM-3在吞噬细胞清除凋亡细胞中起着至关重要的作用。此外，凋亡细胞的TIM-3依赖的吞噬作用对于死亡细胞相关抗原的交叉呈递至关重要。另一方面，发现TIM-2在B细胞上表达，并诱导阳性信号进入B细胞。因此，给予激动型抗TIM-2抗体显著加重了II型胶原诱导的关节炎。接下来，我们研究了自噬在肥大细胞发育和功能中的作用。我们发现，在全营养条件下，肥大细胞可以结构性地将I型轻链转化为II型轻链(Lc3)-II，这是自噬的一个标志，Lc3-II定位于肥大细胞的分泌颗粒中。虽然ATG7基因缺失不影响骨髓基质细胞的发育，但ATG7(-/-)骨髓基质细胞表现出严重的脱颗粒障碍，但不能在抗原刺激下产生细胞因子。

Members of the T-cell immunoglobulin mucin (Tim) family control a variety of immune responses including Th1 and Th2 differentiation of T cells. We found that TIM-3 was expressed on C8+ dendritic cells (DC) and TIM-3 was crucial for clearance of apoptotic cells by phagocytes. Moreover, TIM-3-dependent phagocytosis of apoptotic cells was crucial for cross-presentation of dying cell-associated antigens. On the other hand, TIM-2 was found to be expressed on B cells and induced positive signals into B cells. Therefore, administration of agonistic anti-TIM-2 antibody significantly exacerbated type II collagen-induced arthritis. We next investigated a role for autophagy in the development and function of mast cells. We found that conversion of type I to type II light chain (LC3)-II, a hallmark of autophagy, was constitutively induced in mast cells under full nutrient conditions, and LC3-II localized in secretory granules of mast cells. Although deletion of Atg7 did not impair the development of BMMCs, Atg7(-/-) BMMCs showed severe impairment of degranulation, but not cytokine production upon antigen stimulation.