Macrophages of embryonic origin function during early life to determine host iNKT cell levels at barrier surfaces III
Ontology highlight
ABSTRACT: It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes is unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic, but not bone-marrow derived, macrophages which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later life susceptibility or resistance to iNKT cell associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota and reveal an important post-natal function of macrophages that emerge in fetal life.
Project description:It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes is unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic, but not bone-marrow derived, macrophages which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later life susceptibility or resistance to iNKT cell associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota and reveal an important post-natal function of macrophages that emerge in fetal life.
Project description:It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes is unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic, but not bone-marrow derived, macrophages which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later life susceptibility or resistance to iNKT cell associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota and reveal an important post-natal function of macrophages that emerge in fetal life.
Project description:To investigate local immune mechanisms of intrauterine fetal demise (IUFD), we used the CBA mouse strain, which naturally has mid-late gestation fetal loss. We performed a Treg adoptive transfer and interrogated both pregnancy outcomes and the impact of systemic maternal Tregs on mucosal immune populations at the maternal-fetal interface. Treg transfer prevented fetal loss and increased an MHC-IIlow population of uterine macrophages. Single-cell RNA-sequencing was utilized to precisely evaluate the impact of systemic Tregs on uterine myeloid populations. A population of C1q+, Trem2+, MHC-IIlow uterine macrophages were increased in Treg-recipient mice. The transcriptional signature of this novel uterine macrophage subtype is enriched in multiple studies of human healthy decidual macrophages, suggesting a conserved role for these macrophages in preventing fetal loss.
Project description:Despite their importance in lung health and disease, it remains unknown how human alveolar macrophages develop early in life. In this study we identified the fetal progenitor of human alveolar macrophages. We used microarray to define the gene signatures of human CD14+ blood monocytes (adult AM precursors), CD116+CD64+ fetal liver monocytes, and CD116+CD64- fetal AM precursors.
Project description:iNKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX deficient iNKT cells exhibit impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. Notably, we identified JunB as a novel regulator of iNKT development that partners with UTX to establish an iNKT lineage specific gene expression program. Moreover, we demonstrate that UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment. These findings uncover how UTX regulates iNKT cell development through multiple epigenetic mechanisms.
Project description:We confirm previous findings that adipose iNKT cells are transcriptionally distinct from canoncial splenic iNKT cells and we demonstrate that the adipose iNKT cell population is hetergeneous, containing two major functional subsets which can be segregated by expression of the surface marker NK1.1 (Klrb1c). Both of these adipose iNKT cell subsets play a role in the regulation of adipose tissue tissue homeostasis, including NK1.1+ iNKT cells, which produce IFNγ and induce adipose NK cell-mediated killing of adipose tissue macrophages.