{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTIM‐4 (encoded by TIMD4) is best known as a phosphatidylserine receptor expressed primarily on antigen‐presenting cells such as macrophages and dendritic cells. Its extracellular immunoglobulin (IgV) domain forms a metal‐ion–dependent binding site that specifically recognizes phosphatidylserine displayed on apoptotic cells, thereby tethering them for subsequent engulfment. This “tethering” function is critical to efficient efferocytosis and subsequent maintenance of tolerance, as TIM‐4‐mediated clearance of dying cells helps regulate T‐cell contraction during the post–antigen clearance phase and can even trigger apoptosis of activated Th1 cells via interactions with TIM‐3. In some contexts, proteolytic shedding by ADAM10/17 generates soluble TIM‐4 that retains phosphatidylserine binding and may serve as a negative regulator of cellular TIM‐4 function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in apoptotic cell clearance, TIM‐4 has emerged as an important player in the regulation of immune responses to pathogens and tumors. Studies have demonstrated that TIM‐4 can interfere with the life cycles of enveloped viruses—including HIV‐1, Ebola virus, and others—by binding virion‐associated phosphatidylserine and thereby modulating viral entry and release. In the tumor microenvironment, high TIM‐4 expression on cavity‐resident macrophages and even on certain tumor cells correlates with impaired anti‐tumor T‑cell responses and enhanced tumor growth, illustrating that TIM‐4 contributes to tumor tolerance. Moreover, TIM‐4 expressed on tumor‐associated macrophages has been implicated in promoting metabolic adaptations that favor tumor progression, while its interactions with other transmembrane proteins (for example, EphA2) may modulate tumor cell behavior."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "18"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have linked TIMD4 polymorphisms to a wide spectrum of human diseases. Variants near or within TIMD4 have been associated with altered lipid profiles—including changes in triglyceride, LDL‐, and HDL‐cholesterol levels—which in turn affect cardiovascular disease risk. Furthermore, dysregulated TIM‐4 expression or function has been observed in several immune‐mediated disorders such as systemic lupus erythematosus, rheumatoid arthritis, allergic asthma, and even ulcerative colitis, suggesting its pivotal role in modulating adaptive immunity and inflammatory responses. Additional reports have implicated TIM‐4 in chronic inflammatory settings ranging from ankylosing spondylitis and sepsis‐induced immunosuppression to airway remodeling in chronic rhinosinusitis with nasal polyps, thereby underscoring the multifunctional and context‐dependent nature of TIM‐4 in human pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "35"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Norimoto Kobayashi, Piia Karisola, Victor Peña-Cruz, et al. 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