TIM-3 Regulates Innate Immune Cells To Induce Fetomaternal Tolerance

Abstract

TIM-3 is constitutively expressed on subsets of macrophages and dendritic cells. Its expression on other cells of the innate immune system and its role in fetomaternal tolerance has not yet been explored. Here we investigate the role of TIM-3 expressing innate immune cells in the regulation of tolerance at the fetomaternal interface (FMI) using an allogeneic mouse model of pregnancy. Blockade of TIM-3 results in accumulation of inflammatory granulocytes and macrophages at the utero-placental interface and up regulation of pro-inflammatory cytokines. Furthermore, TIM-3 blockade inhibits the phagocytic potential of uterine macrophages resulting in a build up of apoptotic bodies at the utero-placental interface that elicits a local immune response. In response to inflammatory cytokines, Ly-6ChiGneg M-MDSCs (monocytic myeloid derived suppressor cells) expressing iNOS and arginase 1 are induced. However, these suppressive cells fail to down-regulate the inflammatory cascade induced by inflammatory granulocytes (Ly-6Cint Ghi) and apoptotic cells; the increased production of IFNγ and TNFα by inflammatory granulocytes leads to abrogation of tolerance at the fetomaternal interface and fetal rejection. These data highlight the interplay between cells of the innate immune system at the FMI and their influence on successful pregnancy in mice.

Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3)

“…Our study here provides direct evidence that Tim-3 expressed on microglia mediates the activation of microglia and consequently negatively impacts the survival of neurons and the differentiation of NG2 cell into oligodendrocyte. In addition, consistent with other studies showing Tim-3 participates in the clearance of apoptotic cells [30,31], we demonstrated that Tim-3 is involved in the microglial phagocytosis of apoptotic neurons. A recent study reported that ablation of Tim-3 on microglia does not significantly influence the disease onset, or severity of EAE during a 6-day period of observation [19].…”

“…On the contrary, a recent study demonstrated that blockade and/or downregulation of Tim-3 led to increased peritoneal macrophage activation, whereas Tim-3 overexpression in peritoneal macrophages significantly suppressed TLR-mediated proinflammatory cytokine production, indicating that Tim-3 is a negative regulator of TLR-mediated immune responses [32]. Furthermore, Chabtini et al [31] showed that Tim-3 blockade inhibited the phagocytic potential of uterine macrophages. Microglia have been regarded as resident macrophage of the CNS.…”

“…Apoptotic neurons and secondary necrotic cells releasing intracellular contents could be auto-antigens, and microglia, the brain phagocytes must engulf these dying cells rapidly and efficiently to prevent detrimental inflammatory responses and autoimmunity [29]. Studies have shown that Tim-3 was involved in the phagocytosis process of a subset of peritoneal macrophage, spleen dendritic cells and urine macrophages [30,31]. So we asked whether Tim-3 was also involved in the clearance of apoptotic neurons by microglia.…”

Sphingolipid Pathway Regulates Innate Immune Responses at the Fetomaternal Interface during Pregnancy

“…Multiple mechanisms have been proposed to operate in this process, including complement system, catabolism of tryptophan by indoleamine 2,3-dioxygenase, regulatory T cells, natural killer (NK) 2 cells, macrophages, and dendritic cells (1,2). Notably, a recent study implicated granulocytes in fetomaternal tolerance (3). Maternal decidual tissues play a critical role in this process, as indicated by the fact that pregnancy losses occur during the process of decidualization when endometrial stromal cells surrounding implanting blastocysts undergo dramatic transformation (4,5).…”

Feto-maternal immune regulation by TIM-3/galectin-9 pathway and PD-1 molecule in mice at day 14.5 of pregnancy

“…Mounting evidence supports the crucial role of TIM-3 in regulating immune responses [4] but the in vivo function of this receptor is still poorly understood. Using an allogeneic mouse model of pregnancy Chabtini et al examined the TIM-3 expression on antigen presenting myeloid cells and indicated their possible role in the regulation of tolerance at the fetomaternal interface [5].…”