Distinct Functional Programs in Fetal T and Myeloid Lineages

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 ​(Figure1A).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 ​(Figures11B,C). Figure 1 Models of human immune development. Throughout different stages of development, fetal T and myeloid cells, as compared to their adult counterparts, specifically populate a subset of tissues including the epithelium (DETC, non-DETC cells, and Langerhans ... Fetal T Cell Development and Function Early work in quail chick embryos demonstrated that thymic T cell development occurs in sequential waves, each of which can be identified by differential stem cell colonization of thymic tissue and by unique TCRs (10). These waves appear to be developmentally regulated as they wax and wane according to embryonic gestational age (10), and further work in mice has identified discrete TCR (γδ) utilization during fetal and neonatal development as compared to the adult TCR (αβ) (11–15). Fetal-derived γδ T cells have limited TCR diversity, suggesting a distinct and limited antigen recognition repertoire (12). Furthermore, these cells appear to localize to specific tissues, including the epithelium (16) and the intestine (17). This localization and restricted TCR repertoire suggest that these fetal-derived cells may play a unique role in barrier sites and, as they are developmentally restricted, may be important for promoting tolerance to skin and gut microbiota in early life. Because of their distinct TCR repertoire and anatomical location, multiple fetal-derived functional populations have been characterized in mice, including dendritic epidermal T cells (DETCs) and non-DETC γδ T cell populations found in the dermis (18, 19). DETCs are the first T cells and seed the epidermis early in development (20). These cells have been implicated in the inhibition of inflammatory skin conditions (21), protection against cutaneous malignancies (22, 23), and wound repair (24, 25). Non-DETC γδ T cell populations have been shown to be the primary producers of IL-17 (18, 19) in the skin and may play a role in response to infection. These functions may be indicative of a fetal-specific program, ontologically geared toward appropriate development and maintenance of in utero tolerance. Work in humans has demonstrated that while fetal T cells are capable of recognizing and responding to alloantigen in utero (1), these cells preferentially differentiate into T regulatory (Treg) cells, capable of suppressing immune responses (1, 26). Furthermore, these studies show that the fetal T cells are derived from a fetal hematopoietic stem/progenitor cell (HSPC) in the fetal liver and fetal bone marrow, which gives rise to downstream progeny that are distinct from those generated by adult bone marrow-resident HSPC. Taken together, these data suggest that there are developmentally restricted windows of T cell development in which fetal T cells, functionally distinct from their adult counterparts, arise from discrete HSPC, and seed specific anatomical locations (Figure ​(Figure11B,C).