The transcription factor NR4A1 is essential for the development of a novel macrophage subset in the thymus

Abstract

Tissue macrophages function to maintain homeostasis and regulate immune responses. While tissue macrophages derive from one of a small number of progenitor programs, the transcriptional requirements for site-specific macrophage subset development are more complex. We have identified a new tissue macrophage subset in the thymus and have discovered that its development is dependent on transcription factor NR4A1. Functionally, we find that NR4A1-dependent macrophages are critically important for clearance of apoptotic thymocytes. These macrophages are largely reduced or absent in mice lacking NR4A1, and Nr4a1-deficient mice have impaired thymocyte engulfment and clearance. Thus, NR4A1 functions as a master transcription factor for the development of this novel thymus-specific macrophage subset.

Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors

“…Given the rarity of T-IPs and what appears to be a rather restricted myeloid potential, this is unlikely to represent a significant pathway for extra-thymic myelopoiesis. However, since the Rag1- Cre fate mapping suggests that a large fraction of monocytes/macrophages in the embryonic thymus derive from TSPs, similar to granulocytes in the adult thymus20, TSPs might contribute locally towards generation of intra-thymic monocytes/macrophages suggested to play important roles in thymus development and homeostasis18, 19. It is also possible that the sustained myeloid program in TSPs primarily highlights that the final T-lineage-restriction step takes place in the thymus through loss of myeloid lineage potential.…”

“…The lineage potentials of the first thymopoiesis-initiating progenitors (T-IPs), responsible for initiation of embryonic thymopoiesis remain unclear, although the thymus harbors multiple non-T- cell lineages proposed to play a role in supporting T-cell development18, including removal of apoptotic thymocytes by monocytes/macrophages19. In the adult thymus, fate mapping studies suggested that monocytes mostly develop independently of ETPs2, 20, 21, whereas the origin of monocytes/macrophages residing in the embryonic thymus22 remains to be investigated.…”

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

“…Because 94% of thymocytes undergo apoptosis, the thymus has to deal with an inordinate amount of apoptotic cells. Furthermore, depletion of the Nra1-dependent subset of thymic macrophages impairs efferocytosis, increases proinflammatory cytokine production, and accelerates thymic involution (65). Efferocytosis and inflammation resolution are functionally linked processes because clearance of apoptotic bodies initiates M2 polarization of macrophages.…”

The Dynamics of Apoptotic Cell Clearance

“…T lymphocyte development in the thymus results in large numbers of apoptotic T cells, where thymic macrophages, and to a lesser extent dendritic cells, are sparse in numbers (~1% of total thymic cells) but are positioned in small clusters throughout the organ, providing widespread efferocytic coverage through the tissue (Dzhagalov et al, 2013; H.-J. Kim et al, 2010; Tacke et al, 2015). The CD169+ macrophages, the predominant efferocytes in the bone marrow, are located within dense cellular regions adjacent to the sinuses (Bianconi et al, 2013; Morrison and Scadden, 2014).…”

“…Kim et al, 2010; N. D. Kim and Luster, 2015; Muñoz et al, 2015; Newson et al, 2014; Serhan, 2014; Tacke et al, 2015). In addition, tissue damage/infection also attracts circulating myeloid-derived phagocytes into the tissue to clear dying cells.…”