HLA-DR+ leukocytes acquire CD1 antigens in embryonic and fetal human skin and contain functional antigen-presenting cells

Abstract

Adequate numbers and functional maturity are needed for leukocytes to exhibit a protective role in host defense. During intrauterine life, the skin immune system has to acquire these prerequisites to protect the newborn from infection in the hostile external environment after birth. We investigated the quantitative, phenotypic, and functional development of skin leukocytes and analyzed the factors controlling their proliferation and trafficking during skin development. We show that CD45+ leukocytes are scattered in embryonic human skin and that their numbers continuously increase as the developing skin generates an environment that promotes proliferation of skin resident leukocytes as well as the influx of leukocytes from the circulation. We also found that CD45+HLA-DRhighCD1c+ dendritic cells (DCs) are already present in the epidermis and dermis at 9 wk estimated gestational age (EGA) and that transforming growth factor β1 production precedes Langerin and CD1a expression on CD45+CD1c+ Langerhans cell (LC) precursors. Functionally, embryonic antigen-presenting cells (APCs) are able to phagocytose antigen, to up-regulate costimulatory molecules upon culture, and to efficiently stimulate T cells in a mixed lymphocyte reaction. Collectively, our data provide insight into skin DC biology and the mechanisms through which skin DCs presumably populate the skin during development.

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

“…In line with this, sparse studies reported basal GM-CSF synthesis in human and murine skin or colonic mucosa, most predominantly by KCs and fibroblasts (66)(67)(68). Interestingly, Yasmin et al (40) have clearly shown that BMP-7 precedes TGF-b1 during embryonic life, between 8-10 and 9-11 wk estimated gestational age, respectively (69). Both cytokines are still expressed in adult skin basally and suprabasally, respectively (40).…”

Human embryonic epidermis contains a diverse Langerhans cell precursor pool

“…Using immunohistochemistry, we found that skin equivalents express high levels of TGFβ1, although in a different pattern compared with adult skin. In healthy adult skin, TGFβ1 is located exclusively suprabasally (Schuster et al, 2009), whereas in skin equivalents TGFβ1 is also expressed in cells of the basal layer. Interestingly, the basal layer showed varied expression, perhaps reflecting stratification of pre-existing cells in the formation of the epidermis of the skin equivalent rather than development through proliferation attained in normal skin.…”

“…At 7 weeks EGA, the earliest time point where epidermal LC precursors have been identified (Foster et al, 1986), haematopoiesis in humans is active in the yolk sac, the aorta-gonad-mesonephros region and the foetal liver, representing potential sites of origin for these precursors, but inactive in the bone marrow (Tavian and Péault, 2005). Although local proliferation has been described in epidermal leukocytes during the first trimester (Schuster et al, 2009), the type(s) of progenitors that colonize the epidermis and their relationship to haematopoietic stem cells remain unknown. The aim of this study was to further characterize the phenotype of LC precursors in first trimester human epidermis, in particular to analyse co-expression of HLA-DR with various molecules often thought to be present on LC precursors such as CD14, CD36 and CD45, thereby broadening our knowledge about their ontogeny in vivo.…”

“…Our observation that not all HLA-DR-positive (HLA-DR + ) epidermal cells in embryonic human skin express the LC markers CD1a, CD1c or CD207/langerin, prompted us to hypothesize that during ontogeny the LC phenotype is acquired in the epidermis (Schuster et al, 2009), a notion that was recently validated in the murine system (Seré et al, 2012). Owing to this stepwise development of the LC phenotype, it is conceivable that other molecular structures required for the initiation of immune responses including MHC-II molecules (e.g.…”

Human Epidermal Langerhans Cells Replenish Skin Xenografts and Are Depleted by Alloreactive T Cells In Vivo

“…LC proliferation seems to be dependent on signals from keratinocytes. In humans, proliferating LC are also found in the epidermis during the embryonic phase (35). Because the replacement of LC in the human skin by blood-derived precursors has only been studied in the context of allogeneic stem cell transplantation, the role of these precursors for the homoeostasis of LC under physiologic as well as inflammatory conditions remains elusive.…”