Multi-Layered Mechanisms of Immunological Tolerance at the Maternal-Fetal Interface

Pregnancy represents an immunological paradox where the maternal immune system must tolerate the semi-allogeneic fetus expressing paternally-derived Ags. Accumulating evidence over decades has revealed that successful pregnancy requires the active development of robust immune tolerance mechanisms. This review outlines the multi-layered processes that establish fetomaternal tolerance, including the physical barrier of the placenta, restricted chemokine-mediated leukocyte trafficking, lack of sufficient alloantigen presentation, the presence of immunosuppressive regulatory T cells and tolerogenic decidual natural killer cells, expression of immune checkpoint molecules, specific glycosylation patterns conferring immune evasion, and unique metabolic/hormonal modulations. Interestingly, many of the strategies that enable fetal tolerance parallel those employed by cancer cells to promote angiogenesis, invasion, and immune escape. As such, further elucidating the mechanistic underpinnings of fetal-maternal tolerance may reciprocally provide insights into developing novel cancer immunotherapies as well as understanding the pathogenesis of gestational complications linked to dysregulated tolerance processes.