Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9

Abstract

NK-cell function is regulated by the integration of signals received from activating and inhibitory receptors. Here we show that a novel immune receptor, T-cell Ig and mucin-containing domain-3 (Tim-3), is expressed on resting human NK cells and is up-regulated on activation. The NK92 NK-cell line engineered to overexpress Tim-3 showed a marked increase in IFN-␥ production in the presence of soluble rhGal-9 or Raji tumor cells engineered to express Gal-9. The Tim-3 ؉ population of low-dose IL-12/IL-18-activated primary NK cells significantly increased IFN-␥ production in response to soluble rhGal-9, Gal-9 presented by cell lines, and primary acute myelogenous leukemia (AML) targets that endogenously express Gal-9. This effect is highly specific as Tim-3 Ab blockade significantly decreased IFN-␥ production, and Tim-3 cross-linking induced ERK activation and degradation of IB␣. Exposure to Gal-9-expressing target cells had little effect on CD107a degranulation. Reconstituted NK cells obtained from patients after hematopoietic cell transplantation had diminished expression of Tim-3 compared with paired donors. This observation correlates with the known IFN-␥ defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-␥ production, which has important implications for control of infectious disease and cancer. (Blood. 2012;119(13): 3064-3072) IntroductionHuman NK cells are lymphocytes that develop from hematopoietic progenitor cells in the BM and secondary lymphoid tissues. 1 Peripheral blood (PB) NK cells are phenotypically defined as expressing the surface receptor CD56 (neural cell adhesion molecule [NCAM]) and lacking expression of CD3. 2 They mediate their function through the exocytosis of lytic granules that contain perforin and granzymes, 3 the expression of death receptor ligands, 4 the expression of FcR␥III, which mediates Ab-dependent cellmediated cytotoxicity, 5 and the secretion of cytokines and chemokines. 6 As a result, NK cells take part in both the innate and adaptive immune systems and play important roles in the control of viral infections, pregnancy, tumor immunosurveillance, and hematopoietic cell transplantation (HCT). 7,8 The ability of NK cells to differentiate normal healthy cells (self) from virally infected or malignantly transformed cells (nonself) is regulated by a sophisticated repertoire of cell-surface receptors that control their activation, proliferation, and effector functions. [9][10][11] Recently, a novel receptor, T-cell Ig and mucincontaining domain-3 (Tim-3), has been described to have various roles in immune regulation and is highly expressed on NK cells in mice and humans. [12][13][14][15][16][17] Tim-3 is a type I membrane glycoprotein that was first identified as a cell marker of terminally differentiated CD4 ϩ Th1 cells. 18 Galectin-9 (Gal-9), a 40-kDa S-type ␤-galactoside binding lectin, is a known ligand for Tim-3 and is highly expressed in tissues of the immune system, such as the BM, lymph nodes, thymu...

Natural killer cell memory in infection, inflammation and cancer

“…32). Additionally, TIM3 (also known as HAVCR2) 92,93 , which inhibits by a so far undefined mechanism, and the E3 ubiquitin ligase CBL-B, which inactivates the TAM family of receptors (TYRO3, AXL and MER) 94 , have also been shown to inhibit the activation of NK cells. There is emerging evidence that the formation of NK cell memory for HCMV can also occur in individuals carrying a homozygous null allele of KLRC2, which encodes NKG2C 41 .…”

Feto-maternal immune regulation by TIM-3/galectin-9 pathway and PD-1 molecule in mice at day 14.5 of pregnancy

“…However, there are conflicting data surrounding the TIM-3 mediated regulation of innate immunity. In addition to suggesting similar immunosuppressive actions of TIM-3 on innate immune cells, as observed in T cells [14,15], TIM-3 was also found to promote innate immune responses [2,16]. Moreover, several recently published papers report that in reference to viral infections, overexpression of TIM-3 on NK cells was associated with effector dysfunction [17,18].…”

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells

“…Among innate immune cells, NK cells and some kinds of myeloid cells, including monocytes/macrophages, dendritic cells and mast cells, express TIM-3 in both humans and mouse. In NK cells, TIM-3 is shown to be an inducible surface receptor on activation [27,28], but its function remains controversial. Gleason et al [27] reported TIM-3 as a human NK cell co-receptor to enhance IFN-c production, whereas Ndhlovu et.al reported the inhibition of NK cellmediated cytotoxicity by TIM-3 cross-linking [28].…”