Tim-3+ decidual Mφs induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132

T-cell immunoglobulin mucin-3 (Tim-3) plays roles in the functional regulation of both adaptive and innate immune cells and is greatly involved in many diseases. However, the precise roles of Tim-3 on macrophages (M phi s) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3(+) decidual M phi s (dM phi s) in response to trophoblasts. The reduced abundance of Tim-3 on M phi s was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3(+)M phi s, but not Tim-3(-)M phi s, relieved murine embryo absorption induced by M phi depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3(+) and Tim-3(-)dM phi s were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) M phi s. However, with higher CD132 expression, Tim-3(+)dM phi s subset induced Th2 and Treg bias in decidual CD4(+)T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dM phi function and maintaining normal pregnancy, and suggested that Tim-3 on M phi s is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3(-)M phi s could rescue the fetal resorption induced by M phi depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.

Automated summary

This study reveals the significant roles of Tim-3 in regulating macrophage function during pregnancy and its importance in maintaining normal pregnancy. The expression of Tim-3 on decidual macrophages is closely related to immune regulation between decidual cells and promotes pregnancy stability.