TIMD4

T-cell immunoglobulin and mucin domain containing 4 (TIMD-4) also known as T-cell membrane protein 4 (TIM-4) is a protein in humans that is encoded by the TIMD4 gene.^[5] TIM-4 genes are in mouse present on chromosome 11B1.1 and in humans on chromosome 5q33.2. TIM-4 contains IgV domain with integrin-binding site as well as a unique metal-ion-dependent ligand binding site for phosphatidylserine.^[6] TIM-4 also contains mucin domain with high levels of O-glycosylation. In comparison to other TIM proteins (such as TIM-1, TIM-2...) it does not contain a tyrosine-phosphorylation motif in its intracellular tail domain.^[7]

TIMD4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5F7H, 5DZN, 5F7F
Identifiers
Aliases	TIMD4, SMUCKLER, TIM4, T-cell immunoglobulin and mucin domain containing 4, T cell immunoglobulin and mucin domain containing 4
External IDs	OMIM: 610096; MGI: 2445125; HomoloGene: 51381; GeneCards: TIMD4; OMA:TIMD4 - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q33.3 Start 156,919,292 bp[1] End 156,963,226 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B1.1 Start 46,701,627 bp[2] End 46,735,159 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left testis right testis sperm lymph node testicle oocyte trabecular bone synovial joint gonad superficial temporal artery Top expressed in spleen secondary oocyte mesenteric lymph nodes zygote primary oocyte subcutaneous adipose tissue mammary gland white adipose tissue embryo liver More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 91937 276891 Ensembl ENSG00000145850 ENSMUSG00000055546 UniProt Q96H15 Q6U7R4 RefSeq (mRNA) NM_001146726 NM_138379 NM_178759 RefSeq (protein) NP_001140198 NP_612388 NP_848874 Location (UCSC) Chr 5: 156.92 – 156.96 Mb Chr 11: 46.7 – 46.74 Mb PubMed search [3] [4]
Wikidata
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TIM-4 expression and function

Unlike other TIMs that are mainly expressed on T cells TIM-4 is expressed on APCs such as dendritic cells or macrophages.^[7] TIM-4 serves as a ligand for TIM-1^[8] but also as a receptor for phosphatidylserine. Its phosphatidylserine binding however does not mediate signalling instead it works more as a tethering receptor.^[9] Its phosphatidylserine binding properties also play an important role in removal of apoptotic cells.^[10] Moreover recognition of phosphatidylserine also helps to control adaptive immune system by clearing phosphatidylserine expressing apoptotic T cells. That leads to the regulation of antigen specific memory T cells.^[11] TIM-4 is also able to inhibit naive T cells by non-TIM-1 receptor binding^[12] but once T cells are active TIM-4 works as positive regulator helping to maintain their activity.^[13][14] TIM-4 expression on macrophages plays an important role in their homeostatic maintenance.^[15]

Role in diseases and possible clinical use

It was shown that TIM-4 plays a role in Th2 development. As such it plays a role in the development of allergies and might be a target for future therapies.^[16][17] TIM-4 also mediates autophagy at the site of tumor, which leads to reduced antigen presentation leading to increased toleration of tumor by the immune system.^[18] Therefore there are studies using the blockade of TIM-4 as a complementary therapy for cancer treatment.^[19]