Establishment of tissue-resident immune populations in the fetus

Abstract

The immune system establishes during the prenatal period from distinct waves of stem and progenitor cells and continuously adapts to the needs and challenges of early postnatal and adult life. Fetal immune development not only lays the foundation for postnatal immunity but establishes functional populations of tissue-resident immune cells that are instrumental for fetal immune responses amidst organ growth and maturation. This review aims to discuss current knowledge about the development and function of tissue-resident immune populations during fetal life, focusing on the brain, lung, and gastrointestinal tract as sites with distinct developmental trajectories. While recent progress using system-level approaches has shed light on the fetal immune landscape, further work is required to describe precise roles of prenatal immune populations and their migration and adaptation to respective organ environments. Defining points of prenatal susceptibility to environmental challenges will support the search for potential therapeutic targets to positively impact postnatal health.

Keywords: Embryogenesis; Fetal immunity; Immune ontogeny; Prenatal development.

Fig. 1

Tissue-resident immune populations and functional features in human fetuses. While still incomplete, the current landscape of innate and adaptive immune populations residing in developing tissues during the first and second trimester indicates their role in organogenesis while providing protective/reactive and tolerogenic immunity. Representative seminal evidence is shown. Tissue-resident macrophages adopt specialized phenotypes supporting their niche development, including microglia in the central nervous system [2], Langerhans cells (LC) in skin [44], Kupffer cells in the liver [12], stromal macrophages (MΦ) in the bone marrow [23], and potentially red pulp [55] and alveolar macrophages (AM) [108, 117]. Similarly, innate lymphoid cells (ILC), bona fide tissue-resident cells, are distributed across tissues displaying site-specific phenotypes with as yet incompletely characterized function during fetal life [63]. Lung NK cells possess potent antibody (Ab)- and cytokine-induced cytotoxicity, yet are biased towards tolerating HLA^neg cells [3]. In the skin, mature mast cells are sensitized towards allergens via IgE [186], and differentiation of erythroid progenitors might supplement fetal liver erythropoiesis [12]. Innate-like B1 B cells are prominent in the fetal liver and bone marrow, concomitant with naive and memory B-2 B cells [61, 62], while B cell clonality in the gut is primarily private, and not shared between individuals [82]. B cell lineage expansion occurs in the second trimester bone marrow [23]. Spleen dendritic cells (DC) have antigen-presentation capacity, supporting tolerogenic T cell responses [110]. T cells have an innate-like, fast-response phenotype (invariant γδ T cells) in the thymus [59, 229], skin [73], and intestine [59], however, are strongly biased towards mediating (maternal) tolerance [66, 71, 75], yet show TCR diversity [67, 82] and effector memory [5, 67, 82] in the mucosal surface of the gut. Cord blood CD71⁺ erythrocytes (not shown) are perinatal immunosuppressors, potentially derived from fetal liver erythroid precursors [12, 244, 245]. Created with BioRender.com