Emerging Tim-3 functions in antimicrobial and tumor immunity

Abstract

T cell immunoglobulin-3 (Tim-3) has been identified as a marker of differentiated interferon-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 promoting the development of CD8(+) T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. In contrast to this inhibitory effect on T cells, Tim-3-Gal-9 interaction promotes macrophage clearance of intracellular pathogens. Here, we focus on the emerging role for Tim-3 in tumor and antimicrobial immunity.

Figure 1

Model of Tim-3 function in the immune response (a) In acute inflammation, Tim-3 is expressed on terminally differentiated IFN-γ producing CD4⁺ and CD8⁺ T cells. Upon recognition of its ligand, galectin-9, Tim-3 expressing T cells undergo apoptosis. (b), In chronic inflammation, Tim-3 is co-expressed with PD-1 on dysfunctional or “exhausted” CD8⁺ T cells. Combined targeting of both the PD-1–PD-L1 and Tim-3–Tim-3L pathways successfully restores CD8⁺ T cell effector function and ameliorates chronic disease. (c), Tim-3 on T cells interacts with Gal-9 on MDSC precursors to promotes MDSC expansion, which in turn suppresses T cell responses. (d), Tim-3 on CD4⁺ T cells can also act to facilitate killing of intracellular pathogens in macrophages through interaction with gal-9 and a mechanism involving IL-1β and caspase-1. Overall, Tim-3 on CD4⁺ and CD8⁺ T cells harnesses multiple mechanisms to negatively regulate effector T cell responses and to terminate IFN-γ–mediated inflammation while preserving or enhancing the ability of innate cells to kill intracellular pathogens.