T cell immunoglobulin-3 (Tim-3) was identified as a marker of differentiated IFN-γ-producing CD4+ T helper type 1 and CD8+ T cytotoxic type 1 cells. The interaction of Tim-3 with its ligand, galectin-9 (Gal-9), induces cell death and in vivo blockade of this interaction results in exacerbated autoimmunity and abrogation of tolerance in experimental models, establishing Tim-3 as a negative regulatory molecule. Recent studies have uncovered additional mechanisms by which Tim-3 negatively regulates T cell responses, such as by promoting the development of CD8+ T cell exhaustion and inducing expansion of myeloid-derived suppressor cells (MDSC). In contrast to this inhibitory effect on T cells, Tim-3-Gal-9 interaction promotes macrophage clearance of intracellular pathogens. Here, we will focus on the emerging role for Tim-3 in tumor and anti-microbial immunity.

The interaction between Tim3 on Th1 cells and galectin-9 on Mycobacterium tuberculosis–infected macrophages restricts the bacterial growth by stimulating caspase-1–dependent IL-1β secretion.

In vivo control of Mycobacterium tuberculosis (Mtb) reflects the balance between host-immunity and bacterial evasion strategies. Effector TH1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent over exuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to down regulate TH1 responses, we recently described that its interaction with Galectin-9 expressed by Mtb infected macrophages stimulates IL-1β secretion, which is essential for survival in the mouse model. Why IL-1β is required for host resistance to Mtb infection is unknown. Here we show that IL-1β directly kills Mtb in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1β and downstream TNF production leads to caspase-dependent restriction of intracellular Mtb growth.