Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development

Abstract

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells. Although the thymic medulla consists mostly of developing and mature AIRE epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.

Opposing peripheral fates of tissue‐restricted self antigen‐specific conventional and regulatory CD4+ T cells

“…Although we could not detect USA antigen expression in the thymi of Vil-USA mice by RT-PCR, it is still possible that 2W:I-A bspecific T cell deletion was mediated by very low levels of antigen expressed due to leakiness of the transgene. Of particular note, a recent study identified a rare subset of antigen-presenting cells in the thymus that are highly related to intestinal tuft cells [17].…”

A cell atlas of human thymic development defines T cell repertoire formation

“…After 8 PCW, developmental age was estimated from measurements of foot length and heel to knee length and compared against a standard growth chart (55). A piece of skin, or where this was not possible, chorionic villi tissue, was collected from every sample for Quantitative Fluorescence-Polymerase Chain Reaction analysis using markers for the sex chromosomes and the following autosomes: 13,15,16,18,21,22, which are the most commonly seen chromosomal abnormalities.…”

“…Seminal experiments in animal models have provided major insights into the function and cellular composition of the thymus (12,13). More recently, scRNA-seq has revealed new aspects of thymus organogenesis and new types of thymic epithelial cells (TECs) in mouse (14)(15)(16). However, the human organ matures in a mode and tempo that is unique to our species (17)(18)(19), calling for a comprehensive genome-wide study for human thymus.…”

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

“…These include FBXO3 (F‐box protein 3 E3), which ubiquitinates AIRE and regulates its transcriptional activity, SIRT1 (Sirtuin 1), which is abundantly found in mTECs where it acetylates Aire and regulates the expression of Aire‐dependent TSA‐encoding genes, and HIPK2 (homeodomain‐interacting protein kinase 2), which phosphorylates AIRE and suppresses its coactivator activity, although its impact on the expression of Aire‐dependent TSA‐encoding genes in mTECs is modest . HIPK2 was recently shown to also modulate the development of thymic tuft cells, which represent a subset of thymic epithelial cells that rely on the taste chemosensory molecule TRPM5 for their thymic function and pass through an Aire‐dependent phase for their thymic development . Moreover, the lysyl‐hydroxylase Jmjd6 (Jumonji domain‐containing protein 6) affects splicing of intron 2 of the Aire gene and is required for expression of mature Aire in mTECs, and Dgcr8 (DiGeorge syndrome critical region gene 8) is important for accumulation of Aire‐expressive mTECs in the thymus .…”