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Maternal immune adaptation to accommodate pregnancy depends on sufficient availability of regulatory T (Treg) cells to enable embryo implantation. Toll-like receptor 4 is implicated as a key upstream driver of a controlled inflammatory response, elicited by signals in male partner seminal fluid, to initiate expansion of the maternal Treg cell pool after mating. Here, we report that mice with null mutation in  Tlr4  ( Tlr4   −/−  ) exhibit impaired reproductive outcomes after allogeneic mating, with reduced pregnancy rate, elevated mid-gestation fetal loss, and fetal growth restriction, compared to  Tlr4  +/+  wild-type controls. To investigate the effects of TLR4 deficiency on early events of maternal immune adaptation, TLR4-regulated cytokines and immune regulatory microRNAs were measured in the uterus at 8 h post-mating by qPCR, and Treg cells in uterus-draining lymph nodes were evaluated by flow cytometry on day 3.5 post-coitum.  Ptgs2  encoding prostaglandin-endoperoxide synthase 2, cytokines  Csf2 ,  Il6 ,  Lif,  and  Tnf , chemokines  Ccl2 ,  Cxcl1 ,  Cxcl2 , and  Cxcl10 , and microRNAs  miR-155 ,  miR-146a , and  miR-223  were induced by mating in wild-type mice, but not, or to a lesser extent, in  Tlr4   −/−   mice. CD4 +  T cells were expanded after mating in  Tlr4  +/+  but not  Tlr4  −/−  mice, with failure to expand peripheral CD25 + FOXP3 +  NRP1  −   or thymic CD25 + FOXP3 +  NRP1 +  Treg cell populations, and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. We conclude that TLR4 is an essential mediator of the inflammation-like response in the pre-implantation uterus that induces generation of Treg cells to support robust pregnancy tolerance and ensure optimal fetal growth and survival.

Toll-like receptor-4 null mutation causes fetal loss and fetal growth restriction associated with impaired maternal immune tolerance in mice