Thymic macrophages consist of two populations with distinct localization and origin
Abstract
Tissue-resident macrophages are essential to protect from pathogen invasion and maintain organ homeostasis. The ability of thymic macrophages to engulf apoptotic thymocytes is well appreciated, but little is known about their ontogeny, maintenance, and diversity. Here, we characterized the surface phenotype and transcriptional profile of these cells and defined their expression signature. Thymic macrophages were most closely related to spleen red pulp macrophages and Kupffer cells and shared the expression of the transcription factor SpiC with these cells. Single-cell RNA sequencing showed that the macrophages in the adult thymus are composed of two populations distinguished by the expression of Timd4 and Cx3cr1. Remarkably, Timd4+ cells were located in the cortex, while Cx3cr1+ macrophages were restricted to the medulla and the cortico-medullary junction. Using shield chimeras, transplantation of embryonic thymuses, and genetic fate mapping, we found that the two populations have distinct origins. Timd4+ thymic macrophages are of embryonic origin, while Cx3cr1+ macrophages are derived from adult hematopoietic stem cells. Aging has a profound effect on the macrophages in the thymus. Timd4+ cells underwent gradual attrition, while Cx3cr1+ cells slowly accumulated with age and, in older mice, were the dominant macrophage population in the thymus. Altogether, our work defines the phenotype, origin, and diversity of thymic macrophages.
Data availability
The RNA Sequencing data of thymic macrophages and thymic dendritic cells are available at NCBI Gene Expression Omnibus (GEO) as part of GSE122108 and at www.immgen.org. The single cell RNA sequencing data is deposited at NCBI GEO under accession number GSE185460. The source data underlying Fig. 1G and H, Fig. 3B, D, and G, Fig. 5C, F, and I, Fig. 6B, E, G, and I, Fig. 7B, C, D, and G, Fig. 8B, D, E, and F, Fig. 1S4, Fig. 2S1, Fig. 2S2, Fig. 2S3, Fig. 5S1, and Fig. 5S2 are provided in the Source Data files. All other data supporting the findings of this study are available within the article.
-
Single-cell RNA-sequencing of thymic myeloid cells from Csf1rgfp/gfp (MaFIA) and Cd11cyfp/yfp miceNCBI Gene Expression Omnibus, GSE185460.
-
OpenSource Mononuclear Phagocytes ProjectNCBI Gene Expression Omnibus, GSE122108.
Article and author information
Author details
Funding
Ministry of Science and Technology, Taiwan (107-2320-B-010 -016 -MY3)
- Ivan L Dzhagalov
Ministry of Science and Technology, Taiwan (110-2320-B-A49A-521 -)
- Ivan L Dzhagalov
Ministry of Science and Technology, Taiwan (111-2320-B-A49 -031 -MY3)
- Ivan L Dzhagalov
Yen Tjing Ling Medical Foundation (CI-111-6)
- Ivan L Dzhagalov
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee (IACUC) of National Yang Ming Chiao Tung University (animal protocols #1070506, and 1090301). All surgery was performed under Ketamine + Xylazine anesthesia, and every effort was made to minimize suffering.
Copyright
© 2022, Zhou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,264
- views
-
- 454
- downloads
-
- 20
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Developmental Biology
Apical constriction is a basic mechanism for epithelial morphogenesis, making columnar cells into wedge shape and bending a flat cell sheet. It has long been thought that an apically localized myosin generates a contractile force and drives the cell deformation. However, when we tested the increased apical surface contractility in a cellular Potts model simulation, the constriction increased pressure inside the cell and pushed its lateral surface outward, making the cells adopt a drop shape instead of the expected wedge shape. To keep the lateral surface straight, we considered an alternative model in which the cell shape was determined by cell membrane elasticity and endocytosis, and the increased pressure is balanced among the cells. The cellular Potts model simulation succeeded in reproducing the apical constriction, and it also suggested that a too strong apical surface tension might prevent the tissue invagination.
-
- Cancer Biology
- Developmental Biology
Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C (Trp53YC/YC) cells, and Trp53YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53YC/YC male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53YC/YC thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53YC/YC female for 22 Trp53YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53YC/YC female embryos with exencephaly and the death of most Trp53YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53YC/YC weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.