Toll-like receptor signaling in thymic epithelium controls monocyte-derived dendritic cell recruitment and Treg generation

Abstract

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated selfantigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14 + Sirpα + population of monocytederived dendritic cells (CD14 + moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14 + moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25 + Foxp3 + Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14 + moDC, the generation of Tregs, and thereby the establishment of central tolerance.

Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla

“…Although it is not clear which subset of mTECs depends on this signaling pathway, our data identified corneocyte-like/post-AIRE mTECs, which have the highest levels of p53 activity, as an interesting candidate. As for Toll-like receptors, it is possible that this pathway regulates the differentiation of mTEC hi cells into involucrin+ post-Aire cells, similar to what has been shown in mice 56 . Taken together, our analysis thus revealed important information on the process of cell fate commitment in the epithelial compartment.…”

Thymus and autoimmunity

“…Thymic dendritic cells are classified as CD8α + Sirpα -conventional DCs (cDC1s in mice and CD141 + cDCs in humans), CD8α --Sirpα + DCs (cDC2s, including a monocyte-derived CD14 + DC subset [108]) and plasmacytoid DCs (pDCs) [108][109][110]. cDC1s are generated intrathymically from immature precursors recruited to the thymus by mTEC-derived CCL21s [111], while other DCs are attracted from the periphery as mature cells [112,113] by mTEC-derived chemokines, some of which require toll-like receptor 9 (TLR9)/MYD-88 signalling for production [108]. AIRE-dependent mTECs secrete XCL1 [114] that attracts cDCs and facilitates their acquisition of promiscuously expressed antigens from mTECs [45][46][47]115], while pDCs essentially present peripheral antigens [113].…”

Age-Related Changes in Thymic Central Tolerance

“…In addition, mTECs produce chemokines such as XCL1, CCL19, and CCL21 that promote DC medullary recruitment and localization (70,273,274). Moreover, in response to Toll-like receptor (TLR) signaling, mTECs secrete chemokines that recruit CD14+ monocytederived DCs into the medulla to promote Treg generation (275). Thus, mTECs play multifunctional and essential roles in negative selection and Treg generation.…”