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Immunity:TIM-1和TIM-4 结合磷脂酰丝氨酸

来源:科学时报 2008-01-25 09:39

凋亡细胞通过暴露磷脂酰丝氨酸,告诉吞噬细胞“吃掉我”的信息。如果机体失去清除凋亡细胞的能力,将会导致自身免疫性疾病。   

哈佛医学院的Freeman小组首次发现TIM-1和TIM-4  能特异性“识别”磷脂酰丝氨酸,从而介导凋亡细胞的清除。TIM-4高表达于巨噬细胞和树突状细胞上,而TIM-1表达于肾脏的表皮细胞上,并且转染TIM-1或TIM-4的NIH  3T3细胞能有效地吞噬凋亡细胞。这种吞噬作用可以被TIM-1或TIM-4的单克隆抗体所阻断。进一步研究发现,CC’FG配体结合腔是TIM-4所介导的吞噬作用所必需的。   

因此,TIM-1和TIM-4使抗原提呈细胞能有效地清除凋亡细胞,这一发现将有助于今后对凋亡细胞的清除以及外泌小体的释放在免疫反应中的调节作用研究。((王炯坤/编译))

原文链接:http://www.immunity.com/content/article/abstract?uid=PIIS1074761307005468

Immunity, Vol 27, 927-940, 21 December 2007

Article

TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and Mediate Uptake of Apoptotic Cells

Norimoto Kobayashi,1 Piia Karisola,2 Victor Peña-Cruz,1 David M. Dorfman,3 Masahisa Jinushi,1 Sarah E. Umetsu,4 Manish J. Butte,5 Haruo Nagumo,1 Irene Chernova,1 Baogong Zhu,1 Arlene H. Sharpe,5 Susumu Ito,6 Glenn Dranoff,1 Gerardo G. Kaplan,7 Jose M. Casasnovas,8 Dale T. Umetsu,2 Rosemarie H. DeKruyff,2 and Gordon J. Freeman1,

1 Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
2 Division of Immunology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
3 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
4 Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, Harvard Medical School, Boston, MA 02115, USA
5 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
6 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
7 Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
8 Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autonoma, 28049 Madrid, Spain

Corresponding author
Gordon J. Freeman
gordon_freeman@dfci.harvard.edu

Summary

The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Here we showed that TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4+ peritoneal macrophages, TIM-1+ kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. Mutations in the unique cavity of TIM-4 eliminated PS binding and phagocytosis. TIM-4 mAbs that blocked PS binding and phagocytosis mapped to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.

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