Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation

Abstract

IntroductionApoptosis is a crucial process in the development and homeostasis of multicellular organisms. 1,2 In the immune system, an enormous number of cells undergo apoptosis during development of lymphocytes and after interaction with antigens. 3 Because apoptotic cells and secondary necrotic cells releasing intracellular contents could be autoantigens, phagocytes such as macrophages and dendritic cells (DCs) must engulf these dying cells rapidly and efficiently to prevent detrimental inflammatory responses and autoimmunity. 1,4 To engulf apoptotic cells, macrophages use a variety of molecules, including Mer tyrosine kinase (MerTK), 5 milk fat globule-EGF-factor 8 (MFG-E8), 6 brainspecific angiogenesis inhibitor 1 (BAI1), 7 and T-cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4). 8,9 However, their relative contributions to the phagocytosis remain to be elucidated. Multiple receptors may simultaneously recognize multiple "eat-me" signals on apoptotic cells. In addition, different subsets of macrophages may use different repertoires of receptors for the phagocytosis.DCs are able to not only phagocytose apoptotic cells but also present dying cell-associated antigens with MHC class I molecules, which is termed as "cross-presentation." 1,10 It has been considered that, in steady state, cross-presentation of selfantigens by DCs stimulates CD8 ϩ T cells to proliferate abortively, resulting in their deletion, which is crucial to maintain peripheral tolerance. [10][11][12][13][14] Among mouse splenic DC subsets, CD8 ϩ DCs are unique in their ability for efficient phagocytosis of apoptotic cells and cross-presentation. 15,16 However, the mechanism for the recognition of apoptotic cells by CD8 ϩ DCs is poorly understood. Scavenger receptor CD36 and mannose receptor (MR)/DEC205 are highly expressed on CD8 ϩ DCs, but not CD8 Ϫ DCs, however, these receptors are not required for cross-presentation of cell-associated antigens by this DC subset. [16][17][18] Neither ␣ v ␤ 3 nor ␣ v ␤ 5 integrin that mediates phagocytosis of apoptotic cells by macrophages 1 is essential for phagocytosis by CD8 ϩ DCs. 17 Thus, the phagocytic receptor for apoptotic cells linked to cross-presentation remains to be identified.Tim-3 has been identified as a Th1-specific marker, and several in vivo studies have shown that Tim-3 regulates autoimmunity. 19,20 We and others have reported that Tim-3 negatively regulates Th1-mediated inflammatory diseases such as experimental autoimmune encephalomyelitis (EAE), type I diabetes, and acute graftversus-host diseases (aGVHD). [21][22][23] Moreover, it has been reported that Tim-3 promotes tolerance induction. 21,22 Recently, Zhu et al have identified galectin-9 as a Tim-3 ligand, and they have demonstrated that galectin-9 binds to the carbohydrate chains on Tim-3, and induces cell death of Th1 cells in vitro, which may explain the mechanism by which Tim-3 suppresses Th1 immunity. 24 On the other hand, Anderson et al have reported that Tim-3 is expressed on DCs, and that galectin-9 activate...

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

“…cDNA was synthesized from total RNA using RNase H À reverse transcriptase (Invitrogen) and oligo(dT) [12][13][14][15][16][17][18] (Invitrogen). Amplification of cDNA for Tim3-hIg was performed using primers TIM-3F, 5 0 -GCT AGC ATG TTT TCA GGT CTT ACC CTC AAC TGT G-3 0 , and HIgCR, 5 0 -CGG GAT CCT CAT TTA CCC TGC GAC AG-3 0 .…”

“…Activation of Tim3 inhibits the activity of Th1 cells and production of IFN-c, both of which play important roles in antitumor immunity [7,8]. Tim3, a transmembrane protein that contains an immunoglobulin-and a mucin-like domain, is expressed on many cells including Th1 cells, CD8 T-cells, monocytes, and dendritic cells [9][10][11][12]. Interaction of Tim3 with its ligands, phosphatidylserine and galectin-9, modulates the function of these cells [13,14].…”

“…Interaction of Tim3 with its ligands, phosphatidylserine and galectin-9, modulates the function of these cells [13,14]. Tim3 expressed by monocytes and dendritic cells facilitates phagocytosis of apoptotic cells and up-regulates cross-presentation of apoptotic cell-associated antigens through interaction with phosphatidylserine [12,14]. Galectin-9 induces the death of Th1 cells, which results in the suppression of both Th1 autoimmunity and the generation of Th17 cells [13,15].…”

Activation of mitogen activated protein kinase-Erk kinase (MEK) increases T cell immunoglobulin mucin domain-3 (TIM-3) transcription in human T lymphocytes and a human mast cell line

“…Its expression has been revealed in many other immune cells including macrophages, dendritic cells, natural killer (NK) cells and mast cells (Ju et al, 2010;Sabatos et al, 2003;Wiener et al, 2007). TIM-3 plays important roles in immune responses by modulating functions of these cells through interaction with its ligands: galectin-9 and/or phosphatidyl serine (Nakayama et al, 2009;Zhu et al, 2005).…”

Functional annotation of the T‐cell immunoglobulin mucin family in birds

“…TIM3 was preferentially expressed on Th1 cells; once engaged, it negatively regulated Th1 immunity 5, 6. TIM3 was also expressed on dendritic cells, where it mediated phagocytosis of apoptotic cells and contributed to antigen cross‐presentation 7. TIM4 was also suggested to be expressed exclusively on antigen‐presenting cells (APC), where it contributed to phagocytosis of apoptotic cells and maintenance of tolerance 8, 9.…”