TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
European Journal of Immunology (Impact Factor: 4.03). 09/2009; 39(9):2492-2501. DOI: 10.1002/eji.200939274
Source: PubMed


TIM-3 is a molecule selectively expressed on a subset of murine IFN-gamma-secreting T helper 1 (Th1) cells but not Th2 cells, and regulates Th1 immunity and tolerance in vivo. At this time little is known about the role of TIM-3 on human T cells. To determine if TIM-3 similarly identifies and regulates Th1 cells in humans, we generated a panel of mAb specific for human TIM-3. We report that TIM-3 is expressed by a subset of activated CD4(+) cells, and that anti-CD3/anti-CD28 stimulation increases both the level of expression as well as the number of TIM-3(+) T cells. We also find that TIM-3 is expressed at high levels on in vitro polarized Th1 cells, and is expressed at lower levels on Th17 cells. In addition, human CD4(+) T cells secreted elevated levels of IFN-gamma, IL-17, IL-2, and IL-6, but not IL-10, IL-4, or TNF-alpha, when stimulated with anti-CD3/anti-CD28 in the presence of TIM-3-specific, putative antagonistic antibodies. This was not mediated by differences in proliferation or cell death, but rather by induction of cytokines at the transcriptional level. These results suggest that TIM-3 is a negative regulator of human T cells and regulates Th1 and Th17 cytokine secretion.

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Available from: Terry B. Strom
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    • "Therefore, the connection between TIM-3 and Gal- 9 may function as a negative regulator, dampening Th1-and Th17 driven immune responses and inducing peripheral tolerance by modulating the Th1/Th2 balance [12]. The TIM-3 mediated immunomodulation was first described as a clearly negative regulatory mechanism inducing immunotolerance and T cell apoptosis [13]. However, there are conflicting data surrounding the TIM-3 mediated regulation of innate immunity. "
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    ABSTRACT: Immunoregulation implies the activation of negative pathways leading to the modulation of specific immune responses. Co-inhibitory receptors (such as PD-1 and TIM-3) represent possible tools for this purpose. PD-1 and TIM-3 have been demonstrated to be present on immune cells suggesting general involvement in immunosuppression such as fetomaternal tolerance. The aim of our study was to investigate the expression pattern of PD-1, TIM-3, and its ligand Gal-9 on different immune cell subsets in the peripheral blood and at the fetomaternal interface in pregnant mice. TIM-3 and PD-1 expression by peripheral and decidual immune cells from pregnant BALB-c mice in 2 weeks of gestational age were measures by flow cytometry. Placental galectin-9 expression was determined by immunohistochemically and RT-PCR. Gal-9 was found to be present in the spongiotrophoblast layer of the haemochorial placenta. Decidual NK, NKT and γ/δ T cells showed increased PD-1 expression and reduced cytotoxic potential when compared to the periphery. TIM-3 expression by NK cells and γ/δ T cells is similar both in the periphery and in the decidua, notably, their relative TIM-3 expression is increased locally which is associated with reduced lytic activity. Decidual NKT cells exhibit a reduced TIM-3 expression with increased relative receptor expression and a slightly increased cytotoxicity when compared to the periphery. Our data reveals a particularly complex, tissue and cell type specific immunoregulatory mechanism by the investigated co-inhibitory receptors at the fetomaternal interface. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Placenta
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    • "As expected, it has been shown that TIM-3 blockade accelerates Th1-mediated autoimmune disease in rodent models [48]. Similarly, TIM-3 blocks the secretion of Th1 and Th17 cytokines in human studies, although in this case TIM-3 does not appear to induce cell death [50]. We have shown that blocking TIM-3 by using RMT3-23 blocking antibody accelerates allograft rejection in the absence of CD80/86 and CD28 co-stimulatory signaling [51]. "
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    ABSTRACT: T cell differentiation is dictated by a combination of T cell receptor (TCR) interaction with an antigen-bound major histocompatibility complex (MHC), and co-stimulatory molecules signal. The co-stimulatory signal can be positive or negative, and amplifying or diminishing the initial signal. However, the secondary co-stimulatory signal is not obligatory and its necessity is dictated, in part, by the stage of T cell development. In the field of transplantation, directing the T cell differentiation process can lead to therapeutic possibilities that promote allograft tolerance, and hinder unfavorable alloimmune responses. Therefore, understanding the details of T cell differentiation process, including the influence of co-stimulatory signals, is of paramount importance. It is important to note there is functional overlap between co-stimulatory molecules. It has been observed that some co-stimulatory signals have different effects on different T cell subsets. Hence, blockade of a co-stimulatory signal pathway, as part of a therapeutic regimen in transplantation, may have far reaching effects beyond the initial therapeutic intent and inhibit co-stimulatory signals necessary for desirable regulatory responses. In this review, co-stimulatory molecules involved in the differentiation of naïve T cells into T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), inducible regulatory T cells (iTregs), and T helper 9 (Th9) cells and their overlap are discussed.
    Full-text · Article · Aug 2014 · International Journal of Organ Transplantation Medicine
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    • "However, other data do not support the idea that Tim-3 signaling promotes the activity of DCs. If Tim-3 is a negative regulator of the activation of T cells (1–4), macrophages (6, 7), and monocytes (9), it is not clear why it would be a positive regulator of DC activity (12, 13). Additionally, although Gal-9 induces DC activation, it does not necessarily do so by binding to Tim-3, as it can bind to receptor(s) other than Tim-3 (29, 30). "
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    ABSTRACT: Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss (1) how Tim-3 is expressed and regulated on different innate immune cells; (2) how it affects the activity of different innate immune cells; and (3) how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.
    Full-text · Article · Dec 2013 · Frontiers in Immunology
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