T cell Ig and mucin domain proteins and immunity

Abstract

Proteins of the transmembrane (or T cell) Ig and mucin domain (TIM) family are expressed by multiple cell types within the immune systems of rodents and humans. Studies over the last several years have suggested that these proteins may be promising targets for therapeutic manipulation of immune responses. This review discusses the progress that has been made in understanding TIM protein function in the immune system, as well as some of the unresolved issues that remain on the road to eventually targeting TIM proteins for enhancing or inhibiting immunity.

Figure 1. Domain structures of TIM-1 and TIM-3

The major structural domains of Tim-1 (left) and Tim-3 (right) are shown. The lettering on the IgV domains refers to the structural loops identified in the published crystal structures of this domain from the two proteins (41, 42). Major insertional polymorphisms for both mouse and human Tim-1 are indicated, as are the best-characterized point mutations (PM) of mouse Tim-3. Polymorphisms of human and mouse TIM’s have previously been reviewed in greater detail (12). Likely sites of O- and N-linked glycosylation in the mucin-like and stalk domains, respectively, are also shown. Possible sites of glycosylation within the IgV domains (41, 42) have been omitted for clarity.

Figure 2. Reported ligand interactions with TIM-1 and TIM-3

Shown are the structures of the Tim-1 (A) and Tim-3 (B) IgV domains on two faces as visualized with Cn3D, using structural information from the public database, and described in published reports (41, 42). Residues highlighted in red and yellow in the right-hand panel of Tim-3 (B) indicate sites of N-linked glycosylation and possible galectin-9 binding (42). Arrows indicate the known locations of ligand interactions, based upon mutational, antibody blocking or structural studies. While the mucin domains of TIM proteins can contribute to ligand binding (19), this has not been characterized as well as interactions with the IgV domains. Ligands for which the precise interaction site has not been mapped are indicated in italics, with possible locations of interaction.