Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse.

The T-cell/transmembrane, mucin and immunoglobulin domain protein 1 (TIM-1) is a phosphatidlyserine (PtdSer) receptor and a T cell costimulatory molecule linked to the development of atopic diseases. TIM-1 locates preferentially in intracellular compartments. Here we show that in human and mouse lymphoid cells, TIM-1 localizes in different types of endosomes and that its domain structure is important for protein sorting to intracellular vesicles. The BALB/c mouse TIM-1 protein, which has a longer mucin domain, is sorted more efficiently to endosomes than the shorter C57BL/6 variant. High affinity ligands such as PtdSer increase the amount of cell surface TIM-1; the protein also polarizes toward cell contacts with apoptotic cells. The large pool of intracellular TIM-1 translocates to the immune synapse (IS) with the CD3-TCR (T cell receptor) complex and colocalizes to the central supramolecular activation cluster (cSMAC). In contrast, cell surface TIM-1 does not traffic to the IS, but is located away from it. The bipolar TIM-1 sorting observed during IS formation is determined by differences in its subcellular location, and might modulate antigen-driven immune responses.