T cell immunoglobulin and mucin-domain containing 3 (TIM-3) is a type I transmembrane protein that functions in suppressing immune cell responses and is considered a checkpoint receptor (1,2). TIM-3 is an inhibitory receptor that was first identified as a cell marker for interferon-gamma (IFN-gamma)-producing CD4+ T helper (Th1) and CD8+ T cytotoxic (Tc1) cells (1,2). TIM-3 is also expressed on other immune cell types: regulatory T cells (Treg), natural killer (NK) cells, macrophages, and dendritic cells (DCs), as well as leukemia stem cells (LSCs) (1-3). Human TIM-3 protein is 301 amino acids (aa) in length with a theoretical molecular weight (MW) of 33.4 kDa and shares ~63% aa sequence identity with mouse TIM-3 (2,4). The TIM-3 protein has an extracellular IgV domain, a mucin and stalk domain with O- and N-glycosylation sites, a transmembrane domain, and an intracellular tail with conserved tyrosine residues (2,3). Ligands for TIM-3 include soluble galectin-9, high-mobility group protein B1 (HMGB1), phosphatidylserine (PtdSer), and carcinoembyronic antigen-related cell adhesion molecule-1 (CEACAM-1) (1-3,5). Each of these ligands interact with different regions of the TIM-3 IgV domain. In the absence of ligand binding, the unphosphorylated intracellular tyrosine residues of TIM-3 are associated with HLA-B associated transcript 3 (Bat3), which recruits Lck and this Bat3-Lck complex preserves T cell signaling (1-3,5). When TIM-3 is engaged, an intracellular signaling cascade is initiated to inhibit immune cell activation. (1-3,5). Specifically, the tyrosine residues of TIM-3 are phosphorylated, Bat3 is released, and this results in suppression of immune responses (1-3, 5). Persistent, sustained TIM-3 signaling eventually results in T cell exhaustion (1-3,5).

Dysregulation of TIM-3 expression is associated with autoimmune diseases as shown by studies where inhibition of TIM-3 using blocking antibodies worsened disease progression in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis (MS) (2,3,5). Conversely, high levels of TIM-3 have been shown during viral infection as well as in many cancer types where its increased expression may be an indicator of poor prognosis (2,3,5). TIM-3 has emerged as a potential cancer immunotherapy target as preclinical studies blocking TIM-3 results in increased anti-tumor immunity and prevents tumor growth (3,5). Studies have suggested combination therapy of TIM-3 blockade with blockade of other checkpoint inhibitors such as programmed death 1 (PD-1) or lymphocyte activation gene 3 (LAG-3) is more effective than TIM-3 blockade alone (3,5).

References

1. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020; 8(1):e000911. https://doi.org/10.1136/jitc-2020-000911

2. Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017; 276(1):97-111. https://doi.org/10.1111/imr.12520

3. Joller N, Kuchroo VK. Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol. 2017; 410:127-156. https://doi.org/10.1007/82_2017_62

4. Uniprot (Q8TDQ0)

5. Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020; 20(3):173-185. https://doi.org/10.1038/s41577-019-0224-6

Long Name

T Cell Immunoglobulin Mucin-3

Alternate Names

CD366, HAVcr-2, HAVCR2, KIM-3, SPTCL, TIM3, TIMD3

Gene Symbol

HAVCR2

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Product Specific Notices for TIM-3 Antibody (TIM3/6863R) [Alexa Fluor® 594]

Alexa Fluor (R) products are provided under an intellectual property license from Life Technologies Corporation. The purchase of this product conveys to the buyer the non-transferable right to use the purchased product and components of the product only in research conducted by the buyer (whether the buyer is an academic or for-profit entity). The sale of this product is expressly conditioned on the buyer not using the product or its components, or any materials made using the product or its components, in any activity to generate revenue, which may include, but is not limited to use of the product or its components: (i) in manufacturing; (ii) to provide a service, information, or data in return for payment; (iii) for therapeutic, diagnostic or prophylactic purposes; or (iv) for resale, regardless of whether they are resold for use in research. For information on purchasing a license to this product for purposes other than as described above, contact Life Technologies Corporation, 5791 Van Allen Way, Carlsbad, CA 92008 USA or outlicensing@lifetech.com. This conjugate is made on demand. Actual recovery may vary from the stated volume of this product. The volume will be greater than or equal to the unit size stated on the datasheet.

This product is for research use only and is not approved for use in humans or in clinical diagnosis. Primary Antibodies are guaranteed for 1 year from date of receipt.

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TIM-3 Antibody (TIM3/6863R) [Alexa Fluor® 594]

Novus Biologicals, part of Bio-Techne | Catalog # NBP3-24217AF594

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Background: TIM-3