Beyond T cell exhaustion: TIM-3 regulation of myeloid cells

Abstract

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an important immune checkpoint molecule initially identified as a marker of IFN-γ–producing CD4 + and CD8 + T cells. Since then, our understanding of its role in immune responses has significantly expanded. Here, we review emerging evidence demonstrating unexpected roles for TIM-3 as a key regulator of myeloid cell function, in addition to recent work establishing TIM-3 as a delineator of terminal T cell exhaustion, thereby positioning TIM-3 at the interface between fatigued immune responses and reinvigoration. We share our perspective on the antagonism between TIM-3 and T cell stemness, discussing both cell-intrinsic and cell-extrinsic mechanisms underlying this relationship. Looking forward, we discuss approaches to decipher the underlying mechanisms by which TIM-3 regulates stemness, which has remarkable potential for the treatment of cancer, autoimmunity, and autoinflammation.

β-Catenin in Dendritic Cells Negatively Regulates CD8 T Cell Immune Responses through the Immune Checkpoint Molecule Tim-3

“…We were surprised to observe that β-catenin active cDC1s (cDC1s with active β-catenin, from CD11c-β-catenin active mice) exhibited elevated expression of Tim-3 (Figure 1) in contrast to unchanged or reduced expression of other inhibitory molecules including PD-L1 and Lag3 (Figure S2). The anti-Tim-3 antibody has been tested clinically as a new addition to immune checkpoint blockade immunotherapies [57][58][59], although the mechanism underlying how Tim-3 blockade achieves its anti-tumor effects is not well understood [60]. Of note, we and others have shown that multiple tumors induce up-regulation/activation of β-catenin in DCs, including tumor-infiltrated DCs to restrain anti-tumor CD8 T cell responses [20,21,23,24], raising the intriguing scenario that tumors might exploit the β-catenin/Tim-3 pathway in DCs to suppress anti-tumor CD8 T cell immunity.…”

Immune checkpoint inhibitors: breakthroughs in cancer treatment

“…Subsequently, T cell activation and suppression of the negative regulation of TIM-3 lead to enhanced effector activity of T cells ( Figure 4A ). However, when TIM-3 binds its ligand, Bat-3 dissociates after phosphorylation of Y256/Y263 106 , thus allowing Fyn, another Src kinase, to bind TIM-3. Lck is inactivated, and ZAP70 function is downregulated, thereby ultimately inducing T cell exhaustion 107 .…”