TIM-3 is a receptor for phosphatidylserine and allelic variants differentially mediate uptake of apoptotic cells (130.41)

Abstract

Abstract TIM-3 is a member of the T cell/transmembrane, Ig and mucin (TIM) gene family. TIM-3 is expressed on Th1 cells and dendritic cells and generates an inhibitory signal resulting in apoptosis of Th1 cells. We found that TIM-3 is receptor for phosphatidylserine (PtdSer) exposed on apoptotic cells. A co-crystal structure showed a similar binding mode to TIM-4/PtdSer with a deep binding pocket coordinating calcium ion with PtdSer and flanked by two hydrophobic loops that can extend into a membrane. Fibroblasts transfected with BALB/c TIM-3 more effectively bound to and phagocytosed apoptotic cells than HBA TIM-3 transfected cells. Liposomes containing equal amounts of PtdSer and phosphatidylcholine reduced phagocytosis in a concentration dependent-manner. This suggests that functional differences in TIM-3 alleles may contribute to the Th1/Th2 differences between the strains. T or B cells expressing TIM-3 formed conjugates with but failed to phagocytose apoptotic cells, suggesting a role in signaling in lymphocytes without engulfment. These findings indicate that TIM-3 expressing cells can respond to apoptotic cells through TIM-3/PtdSer binding, 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 TIMs as PtdSer receptors and unify the function of the TIM gene family, which has been associated with ashma and autoimmunity and shown to modulate peripheral tolerance.