T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells.
T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells.
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DOI：
10.4049/jimmunol.0903059
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发表时间：
2010-02-15
期刊：
影响因子：
--
通讯作者：
Casasnovas JM
中科院分区：
文献类型：
--
作者：
DeKruyff RH;Bu X;Ballesteros A;Santiago C;Chim YL;Lee HH;Karisola P;Pichavant M;Kaplan GG;Umetsu DT;Freeman GJ;Casasnovas JM
T细胞/跨膜、IG和粘蛋白（TIM）蛋白，使用哮喘的同类小鼠模型鉴定，关键地调节先天性和适应性免疫。TIM-1和TIM-4是暴露于凋亡细胞表面的磷脂酰丝氨酸（PtdSer）的受体。在此，我们显示与结构和生物学研究，TIM-3也是PtdSer的受体，结合在口袋上的N-末端IgV结构域与钙离子的协调。TIM-3/PtdSer结构与TIM-4/PtdSer结构相似，反映了TIM家族成员保守的PtdSer结合模式。表达小鼠或人TIM-3的成纤维细胞结合并吞噬凋亡细胞，其中小鼠TIM-3的BALB/c等位基因变体显示出比同类C.D2 Es-Hba等位基因变体更高的能力。这些功能差异是由于TIM-3多态性变体的IgV结构域的BC环的结构差异。与成纤维细胞相反，表达TIM-3的T或B细胞与凋亡细胞形成缀合物，但未能吞噬凋亡细胞。总之，这些发现表明，TIM-3表达细胞可以响应凋亡细胞，但PtdSer的TIM-3接合的结果取决于多态性变体和表达TIM-3的细胞类型。这些发现为TIM蛋白作为PtdSer受体建立了一个新的范例，并统一了TIM基因家族的功能，该基因家族与哮喘和自身免疫相关，并显示出调节外周耐受性。
T cell/transmembrane, Ig, and mucin (TIM) proteins, identified using a congenic mouse model of asthma, critically regulate innate and adaptive immunity. TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), exposed on the surfaces of apoptotic cells. Herein, we show with structural and biological studies that TIM-3 is also a receptor for PtdSer that binds in a pocket on the N-terminal IgV domain in coordination with a calcium ion. The TIM-3/PtdSer structure is similar to that of TIM-4/PtdSer, reflecting a conserved PtdSer binding mode by TIM family members. Fibroblastic cells expressing mouse or human TIM-3 bound and phagocytosed apoptotic cells, with the BALB/c allelic variant of mouse TIM-3 showing a higher capacity than the congenic C.D2 Es-Hba–allelic variant. These functional differences were due to structural differences in the BC loop of the IgV domain of the TIM-3 polymorphic variants. In contrast to fibroblastic cells, T or B cells expressing TIM-3 formed conjugates with but failed to engulf apoptotic cells. Together these findings indicate that TIM-3–expressing cells can respond to apoptotic cells, but the consequence of TIM-3 engagement of PtdSer depends on the polymorphic variants of and type of cell expressing TIM-3. These findings establish a new paradigm for TIM proteins as PtdSer receptors and unify the function of the TIM gene family, which has been associated with asthma and autoimmunity and shown to modulate peripheral tolerance.
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