Abstract
T-cell immunoglobulin and mucin domain containing 4 (Tim-4) is a phosphatidylserine receptor and is selectively expressed on antigen presenting cells. Recently, Tim-4 was reported to be expressed on iNKT cells, B1 cells, and tumor cells, suggesting it has multiple biological functions. In this review, we mainly summarize the expression and regulation of Tim-4 in immune cells including T cells, macrophages, dendritic cells, NKT cells, B cells, and mast cells. The expression of Tim-4 in these cells implies that Tim-4 might participate in immune related diseases. Emerging evidence emphasizes a substantial role for Tim-4 in maintaining homeostasis by regulating various immune responses, including viral infection, allergy, autoimmunity, and tumor immunity. Here, we collectively evaluated the role of Tim-4 in health and diseases. This summary will be extremely useful to fully understand the function of Tim-4 in the pathogenesis of immune related diseases, which would provide novel clues for the diagnosis and treatment of diseases.
Highlights
The T cell immunoglobulin domain and mucin domain (Tim) gene family is a relatively new gene family and was discovered in 2001 [1]
This study showed that both immunoglobulin variable region-like (IgV) and mucin domains were required for T-cell immunoglobulin and mucin domain containing 4 (Tim-4) mediated inhibition of T-cell activation and Th17 differentiation via the MAPK pathway [30]
We found that Tim-4 expression was significantly higher in nonsmall-cell lung cancer (NSCLC) tissues, and overexpression of Tim-4 was associated with adverse prognosis
Summary
Tim-4 is highly expressed in peripheral lymphoid tissues, such as the tonsils, thymus, spleen, lymph nodes (LNs), and Peyer’s nodule but is poorly expressed in the lung, liver, and kidney tissues [5, 9, 10]. Li et al [50] found that DC infiltration and Tim-4 expression were increased in hepatic warm ischemia reperfusion (IR) models, and Tim-4 blockade on DCs significantly attenuated hepatic injury and reduced the release of pro-inflammatory cytokines They found that Tim-4 blockade inhibited Th2 cell differentiation and facilitated induced CD4+CD25+Foxp3+ iTreg generation through the IL-4/STAT6 signaling pathway in vitro. The simultaneous exposure to cholera toxin and peanuts resulted in an increase in Tim-4, MHC II, and costimulatory molecules expression in DCs, which could induce differentiation and activation of peanut-specific Th2 cells in the intestine. Xu et al reported that glioma-derived macrophages, expressing high levels of Tim-4, contributed to tumor tolerance by phagocytizing T cells following PS exposure [73]. We speculate that sTim-4 might act as an antagonist of membrane surface Tim-4, which requires further investigation
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