Thymic Macrophage Populations Change with Age

The thymus atrophies with age, limiting the supply of new T cells to support the adaptive immune system. This is an important aspect of immune aging. Digging deeper into the mechanisms of thymus aging is of interest to the extent that it might reveal practical approaches to intervention. The challenge of the thymus is near entirely its inaccessible location, making it hard to deliver the known factors that can induce thymic regrowth without side-effects in the rest of the body. Here, researchers find that one population of macrophages characteristic of thymic tissue diminishes with age, while another population expands. The researchers theorize that it might be possible to adjust these cell proportions to provoke thymic regrowth, but at this stage that proposal is quite theoretical. More research would be needed to validate the underlying hypothesis regarding how these macrophages are involved in either supporting thymic tissue or encouraging atrophy.

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 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.

The clear correlation between the accumulation of Cx3cr1+ thymic macrophages and thymic involution suggests that some factors produced exclusively by these cells are relevant. For example, Cx3cr1+ thymic macrophages are the predominant producer of the growth factor PDGFα that is required for the maintenance of adipocyte stem cells and can stimulate tissue fibrosis. The gradual accumulation of Cx3cr1+ macrophages could increase the availability of PDGFα in the aging thymus stimulating extracellular matrix production and differentiation of precursors into adipocytes. This model predicts that limiting the influx of Cx3cr1+ macrophage precursors could delay thymus involution.