Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity

Abstract

IntroductionNatural killer (NK) cells comprise 5% to 20% of human peripheral blood lymphoid cells and are a critical component of the immune system, providing protection against viral infections and contributing to tumor immune surveillance. NK-cell activity is regulated by an intricate balance of signals transmitted by inhibitory and activating receptors. 1,2 Functionally distinct NK-cell subsets can be defined based on the level of CD56 and CD16 coexpression. 3 CD56 bright CD16 Ϫ NK cells produce abundant IFN-␥ in response to stimulation with interleukin (IL)-12 and proliferate robustly when cultured in IL-2, whereas CD56 dim CD16 ϩ NK cells are more cytolytic and produce significant amounts of cytokine when their activating receptors are engaged. 4 CD56 dim CD16 ϩ NK cells are considered mature NK cells and are differentiated from the immature CD56 bright CD16 -NK-cell subset. This is further supported by recent data demonstrating the dynamics of expression of the killer immunoglobulin-like receptors (KIR), CD57, CD94, and CD62L expression on the CD56 dim CD16 ϩ NK cells as they mature from CD56 bright CD16 -NK-cell precursors. [5][6][7][8][9] T-cell immunoglobulin-and mucin domain-containing (Tim)-3 is a member of Tim family of receptors of which there are 3 in humans (Tim-1, Tim-3, and Tim-4). 10 These molecules are involved in diverse metabolic and immunoregulatory processes. 11 Tim-3 is a type I transmembrane protein that contains no defined signaling motifs in its cytoplasmic domain, but it has been implicated both in activation and inhibition of immune responses 12,13 and in the induction of apoptosis of Tim-3-bearing cells through interactions with galectin-9. 14 Tim-3 is expressed on CD4 ϩ T cells, dendritic cells, monocytes, 15-17 CD8 ϩ T cells, 18,19 and NK cells. 20 In a comparison of lymphocyte populations in healthy human subjects, the highest transcription of the gene encoding Tim-3 was observed in NK cells. 21 There is evidence that engagement of Tim-3 on mouse T cells with the ligand galectin-9 promotes aggregation, leading to the death of T-helper 1 cells and the selective loss of interferon (IFN)-␥-producing T cells. 14 On human T cells, the expression of Tim-3 regulates cell proliferation and IFN-␥ secretion. 19,21,22 We and others have observed that increased amounts of Tim-3 on T cells during HIV, hepatitis C virus, and other chronic viral infections correlated with T-cell dysfunction, suggesting that Tim-3 is part of a negative regulatory pathway. 19,[23][24][25] In this study, we investigated the expression of Tim-3 on human NK cells and its regulation by cytokines, and we provide evidence for the role of Tim-3 in the restraint of NK cell-mediated cytotoxicity in healthy individuals. Methods Primary cells and cell linesPeripheral blood mononuclear cells (PBMCs) of healthy individuals were obtained from the Stanford Blood Bank. Cord blood PMBCs were obtained The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, ...

The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy

“…Tim-3 was found to act as a marker of activation or maturation of NK cells and suppress NK cell cytotoxicity. 25 In contrast, other reports have provided evidence that increased Tim-3 expression on NK cells leads to NK cell dysfunction in chronic virus infections, such as hepatitis B and HIV infection. 26,27 Therefore, we propose that the regulatory effects of Tim-3 on NK cells are distinct in different immune microenvironments.…”

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].…”