Distinct Functional Programs in Fetal T and Myeloid Lineages

INTRODUCTION Pregnancy poses a challenge to normal mechanisms of immune recognition and rejection: both the mother and her fetus are exposed to allogeneic cells from one to the other. In the case of the mother, these cells are fetal cells carrying paternal antigens; in the case of the fetus, they are maternal cells expressing non-inherited maternal alloantigens (1, 2). Since adaptive immune recognition of these alloantigens could result in mutual rejection and an end to the pregnancy, there are extensive mechanisms in place to inhibit such responses, including poor antigen presentation (3), non-canonical MHC expression, and unique placental and decidual immunomodulatory cell populations (4). The reader is referred to several excellent reviews on this subject (4–7). Given the inherent difficulties attending experiments in humans, studies of the fetal–maternal interface have focused primarily on inbred strains of laboratory mice. There are, however, major differences between the biology of immune system development of such mice and that found in humans, making it challenging to relate findings in one species to the other. In mice, by example, mature αβ T cells colonize peripheral lymphoid organs during very late gestation and do not fully populate the periphery until after birth (8). By contrast, mature αβ T cells can be found in the periphery of the human fetus as early as 10–12 gestational weeks (5, 9). Thus, early hypotheses posited that in utero tolerance was maintained by a passive or inert fetal immune system (similar to that found in the mouse) (Figure 1A). However, current research suggests that there exist distinct fetal programs both in the T and myeloid compartments that contribute to the unique environment in utero, both in mice and in humans (Figures 1B,C).