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HAVCR2

Official Full Name
hepatitis A virus cellular receptor 2
Organism
Homo sapiens
GeneID
84868
Background
The protein encoded by this gene belongs to the immunoglobulin superfamily, and TIM family of proteins. CD4-positive T helper lymphocytes can be divided into types 1 (Th1) and 2 (Th2) on the basis of their cytokine secretion patterns. Th1 cells are involved in cell-mediated immunity to intracellular pathogens and delayed-type hypersensitivity reactions, whereas, Th2 cells are involved in the control of extracellular helminthic infections and the promotion of atopic and allergic diseases. This protein is a Th1-specific cell surface protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. [provided by RefSeq, Sep 2011]
Synonyms
TIM3; CD366; KIM-3; SPTCL; TIMD3; Tim-3; TIMD-3; HAVcr-2;
Bio Chemical Class
Immunoglobulin
Protein Sequence
MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHSKEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAMP
Open
Disease
Alzheimer disease, Hodgkin lymphoma, Lymphoma, Myelodysplastic syndrome, Non-small-cell lung cancer, Oral cavity/oesophagus/stomach in situ carcinoma, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
10 +
Discontinued Drug
0

Detailed Information

TIM-3, also known as HAVCR2, is part of the larger TIM (T-cell immunoglobulin and mucin domain) family, which plays varied roles in immune response regulation, across autoimmune diseases, cancer immunosurveillance, and more. In humans, this family includes TIM1, TIM3, and TIM4, located on chromosome 5q33.2. TIM-3's function as an immune checkpoint makes it a significant focus in the field of immunotherapy, especially regarding its regulation of T-cell exhaustion in cancer and chronic viral infections.

Structure and Expression of TIM-3

TIM-3 is a membrane protein comprising an extracellular domain, a transmembrane domain, and a cytoplasmic tail, consisting of 281 amino acids. Comprising an IgV domain with glycosylation sites, the extracellular area helps to interact with many ligands. Several immune cells express TIM-3: Th1 and Th17 helper T-cells, regulatory T-cells (Treg), dendritic cells (DCs), monocytes, and natural killer (NK) cells. Its prevalence in tumor settings is also shown by its presence in tumor-infiltrating lymphocytes (TILs). TIM-3 production in T-cells usually indicates those with compromised function; it is a hallmark of fatigue particularly about malignancies or persistent infections where immune evasion is common.

The Functional Dynamics of TIM-3

TIM-3 interacts with multiple ligands, such as Galectin 9, phosphatidylserine (PtdSer), and CEACAM1, which bind at distinct sites on the IgV domain. Galectin 9 binding may compromise anti-tumor defenses by causing T-cell death and inhibiting Th1-mediated immune responses. Although its precise physiological effect is yet less known, TIM-3 helps to remove apoptotic cells using PtdSer interaction. The association with HMGB1 compromises DNA vaccination effectiveness and chemotherapy results through nucleic acid, hence influencing immune response. TIM-3 is recruited to the immunological synapse of activated T-cells and interacts with BAT3 and LCK kinase to sustain T-cell activation when it is not attached to its ligands.

Figure 1 illustrates models for TIM3-ligand interactions, including TIM3 maintaining T cell activation through BAT3 binding, Galectin 9 binding to TIM3 to promote oligomerization and the formation of other TIM3-ligand complexes, and phosphatidylserine (PtdSer) from apoptotic cells binding TIM3, leading to immune synapse disruption and T cell anergy or apoptosis.Figure 1. Models for TIm3–ligand interactions. (Wolf Y, et al., 2022)

In its inhibitory capacity, TIM-3 plays a crucial role in regulating immune responses by modulating T-cell activity. The inhibition of T-helper type 1 (Th1) lymphocytes diminishes auto- and alloimmune responses, promoting immunological tolerance. Conversely, TIM-3 may provoke immunological responses in some situations by increasing TCR-induced signaling in T-cells, which includes ZAP70, LCK, and FYN. Though it may also reduce NK cell-mediated cytotoxicity in certain inflammatory reactions, TIM-3 works as a coreceptor on innate immune cells like NK cells, hence increasing IFN-gamma generation.

Implications in Disease Contexts

The implications of TIM-3 expression extend to cancer, where it is often associated with immune evasion mechanisms. TIM-3 expression has consequences in cancer as well, where it is usually linked with immune evasion mechanisms. Utilizing T-cell mediated response suppression, lets cancer cells escape immune monitoring, hence promoting disease development and treatment resistance. Often, TIM-3 on T-cells in tumor microenvironments indicates an aberrant immune response.

Apart from cancer, TIM-3 also has a function in infectious pathogens and autoimmune disorders. TIM-3 inhibits autoreactive T-cells, hence helping to minimize immune-mediated tissue damage in autoimmune settings. TIM-3 regulates natural immunity during infections, especially with intracellular pathogens, therefore helping to resolve inflammation. Excessive suppression of immune responses, however, may cause infections to persist as well.

Immunotherapy research depends much on TIM-3, as other immune checkpoints such as CTLA4 and PD-1. Pharmaceutical firms are aggressively looking for TIM-3 targeting therapies given no authorized medications. Focusing on illnesses like acute myeloid leukemia and non-small cell lung cancer, these treatments are in different clinical trial stages. Combining TIM-3 inhibitors with current therapies could provide more therapeutic advantages.

Therapeutic use of TIM-3 and PD-1/PD-L1 pathways together might strengthen immune responses against cancers. Engaging a larger immune assault on cancer cells, several therapeutic studies investigate dual-specific antibodies targeting both TIM-3 and PD-1 or PD-L1. These medicines provide a more complete immune modulation strategy meant to offset adaptive resistance mechanisms seen with anti-PD-1 therapy. Early research has shown encouraging outcomes in lowering tumor loads and increasing immune cell penetration into malignancies.

Prospects and Challenges

While targeting TIM-3 presents considerable promise, challenges remain in understanding its complex biology and interactions. The therapeutic potential of TIM-3 inhibitors, especially in combination with other immunomodulators, continues to attract scientific interest. Researchers are exploring the precise mechanisms by which TIM-3 influences different immune cell types and its role under various pathological conditions to design more effective interventions.

References:

  1. Solinas C, De Silva P, Bron D, et al. Significance of TIM3 expression in cancer: From biology to the clinic. Semin Oncol. 2019;46(4-5):372-379.
  2. Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20(3):173-185.
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