Immune regulation by Tim-3

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.

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

“…Accumulating evidence suggests that TIM-3 is expressed not only on effector T cells, but also in tumor-infiltrating Tregs in multiple tumor types [8,50]. The increased expression of TIM 3 in tumor-infiltrating Tregs are also associated with poor survival [8,9].…”

The co-stimulatory activity of Tim-3 requires Akt and MAPK signaling and immune synapse recruitment

“…The protein T cell (or transmembrane) immunoglobulin and mucin domain 3 (Tim-3) was originally described as a marker for Th1 helper T cells (6). Subsequent studies revealed that Tim-3 is also expressed on acutely activated CD8 + T cells and a subset of regulatory T cells, in addition to various non-T cells, including some macrophages, dendritic cells, NK cells and mast cells (7)(8)(9). However, most of the attention paid to Tim-3 in recent years has focused on the high expression of Tim-3 on "exhausted" CD8 + T cells observed under conditions of chronic infection or within the tumor microenvironment.…”

“…First, there has yet to emerge a clear-cut mechanism by which Tim-3 might transmit an inhibitory signal, for example recruitment of phosphatases like PD-1, or by competition with co-stimulatory receptors, like CTLA-4. Second, at least four ligands have been described to interact with Tim-3, including galectin-9, phosphatidylserine (PS), HMGB1 and CEACAM1 (7)(8)(9), which are known to also interact with other and distinct receptors (15,(17)(18)(19)(20), making the definition of important receptor-ligand interactions difficult at best. Third, studies from multiple labs on both T cells and non-T cells have directly or indirectly demonstrated an ability of Tim-3 to transmit positive, activationpromoting, signals (21)(22)(23)(24)(25)(26).…”

Expression of the Tim3‐galectin‐9 axis is altered in drug‐induced maculopapular exanthema

“…In recent years, inhibitory checkpoint molecules such as Tim3 have received attention due to their critical role in the regulation of both adaptive and innate immune mechanisms . The interaction of this molecule with one of its ligands, Gal9, has been shown to have a crucial role in controlling Th1 and Th17 subpopulations in autoimmune diseases, especially for those with skin involvement .…”

“…They possess either negative or positive function in various settings, depending on the cell type and physiological or pathological context. Moreover, we must take into account that other ligands for Tim3 exist and that Gal9 can bind to other receptors on the cell surface as well . Thus, more actors not included in this study, may be involved in the impaired immune regulation showed in MPE.…”