Developmental and Functional Characterization of Fetal Phagocytes with Dendritic Cell Differentiation Potential

Our previous studies revealed that immunologically immature murine fetuses couldn’t be tricked into tolerating ovalbumin but rather conferred Th2 immunity on account of fetal phagocytes that attenuated proteolysis to sequester internalized ovalbumin for delayed presentation. Given the limited exposure to antigens in utero and immature adaptive immunity, fetuses rely heavily upon their innate immune system for protection against offenders. Thus, macrophage-like fetal phagocytes are deemed as the pivotal member of fetal innate immunity to provide immediate defense that recognize and engulf antigens, and belatedly instruct adaptive immune responses. It is reported that the qualitative differences of macrophages with distinct backgrounds of developmental genetics may contribute to distinct T-cell subtype skewness. Tissue-resident macrophages from yolk sac-derived erythro-myeloid progenitors (EMPs) adopt anti-inflammatory Th2 phenotypes, while passenger macrophages from marrow hematopoietic stem cells always exhibit pro-inflammatory Th1 responses. Based upon the literature review, fetal phagocytes we dealt with are more inclined to originate from yolk sac-derived EMPs that will give rise to tissue resident macrophages. Of note, there is evidence showing that fetal/neonatal T-cells could be switched to either T1 or Th2 responses, relying upon the conditions introduced, such as antigens, adjuvants and antigen presenting cells. Besides, proliferating microglial cells as resident macrophages could lead to neuronal damage as a result of Th1 responses. Thus, it may not be accurate to deem resident macrophages as universally being anti-inflammatory. This proposal is aimed to investigate the origin, migration and development of fetal phagocytes as well as their ability to induce Th1 immune responses. To understand the ontogenic and functional heterogeneity of fetal phagocytic lineages may better comprehend the complex role of these cells in tissue homeostasis and immunity. The information generated will provide an important foundation for developing novel approaches to meet the health challenges of pediatric life, such as enhancing vaccine responsiveness, mitigating pediatric or even fetal-onset allergy, and increasing resistance to pathogenic microorganisms. Immunologically, it will advance our knowledge of handling fetal phagocytes as well as their roles in immune recognition such as autoimmunity and self-nonself discrimination. Therefore, it may pave the way to facilitating transplantation tolerance, or on the other hand to cellular therapies against cancer cells or pathogens given their potent immunogenicity.

Project ID:PC10608-1478
External Project ID:MOST106-2314-B182-055