Abstract
T-cell immunoglobulin and mucin domain 3 (Tim-3) is a transmembrane protein that in both mice and humans has been shown to possess various functions in a context-dependent manner. Thus, Tim-3 has been associated with both inhibitory and co-stimulatory function, depending in part on the specific cell type and immune response course. Though originally described on T cells, Tim-3 is now known to be expressed by both lymphoid and non-lymphoid cells within the immune system and even by non-immune cells. In addition, though widely thought of as a negative regulator of immunity, Tim-3 has been shown in more recent studies to have a positive function on both myeloid and lymphoid cells, including T cells. Tim-3 is often expressed at a high level on exhausted T cells in tumors and chronic infection and may engage in crosstalk with other so-called “checkpoint” molecules such as PD-1. Thus, Tim-3 has emerged as a possible therapeutic target, which is being actively explored both pre-clinically and clinically. However, recent research suggests a more complex in vivo role for this protein, compared with other targets in this area.
Highlights
T-cell immunoglobulin and mucin domain 3 (Tim-3)[1] is an immunoglobulin (Ig) and mucin domain family cell-surface molecule that was originally identified on CD4 helper 1 (Th1) and CD8 T cytotoxic 1 (Tc1) cells[2]
The absence of Tim-3 leads to defective Akt/mTOR signaling[23]; in the chronic lymphocytic choriomeningitis virus (LCMV) T-cell exhaustion model, Tim-3 expression was sufficient to dampen the anti-PD-1 rescue of T-cell responses, thereby suggesting crosstalk of PD-1 and Tim-3 in exhausted T cells[23], as discussed above. Supporting this finding is the recent report by Gorman and Colgan that acute stimulation in response to LCMV infection leads to upregulation of Tim-3 in persisting Th1-type CD4 cells, and these cells show enhanced effector functions both in vitro and in vivo[24]
The same authors previously reported an indirect mechanism for Tim-3 in both mouse and human Mycobacterium tuberculosis (MTb) infection, whereby Tim-3 expressed by T cells interacts with Gal-9, which in turn stimulated the antibacterial function of macrophages[68,69]
Summary
T-cell immunoglobulin and mucin domain 3 (Tim-3) (gene name Havcr2)[1] is an immunoglobulin (Ig) and mucin domain family cell-surface molecule that was originally identified on CD4 helper 1 (Th1) and CD8 T cytotoxic 1 (Tc1) cells[2]. Nuclear factor of activated T cells (NFAT) signaling has been shown to play a role in CD8+ T-cell regulation of Tim-316. Tim-3 is generally co-expressed with other checkpoint receptors in settings of T-cell exhaustion in both tumors and chronic infection in both humans and mice[20].
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