Biology subjects

Voboril, M.

Publications and source records attributed to Voboril, M..

3 recordsLinked to original sources

bioRxiv2025

Thymic DC2 are heterogenous and include a novel population of transitional dendritic cells

Myeloid cells, including dendritic cells (DCs) and macrophages, are essential for establishing central tolerance in the thymus by promoting T cell clonal deletion and regulatory T cell (Treg) generation. Previous studies suggest that the thymic DC pool consists of plasmacytoid DC (pDC), XCR1+ DC1 and SIRP+ DC2. Yet the precise origin, development, and homeostasis, particularly of DC2, remain unresolved. Using single-cell transcriptomics and lineage-defining mouse models we identify nine major populations of thymic myeloid cells and describe their lineage identities. What was previously considered to be "DC2" is actually composed of 4 distinct cell lineages. Amongst these are monocyte-derived DCs (moDC) and monocyte derived macrophages (moMac), which are dependent on thymic interferon to upregulate MHCII and CD11c. We further demonstrate that conventional DC2 undergo intrathymic maturation through CD40 signaling. Finally, amongst "DC2" we identify a novel thymic population of CX3CR1+ transitional DC (tDC), which represent transendothelial DCs positioned near thymic microvessels. Together, these finding reveal the thymus as a niche for diverse, developmentally distinct myeloid cells and elucidate their specific requirements for development and maturation.

immunology↗

bioRxiv2025

Claudin 1-mediated positioning of DC1 to mTECs is essential for antigen transfer-coupled DC1 maturation and maintenance of central tolerance

The mechanisms of central tolerance, which rely on the presentation of self-antigens by medullary thymic epithelial cells (mTECs) and DCs, prevent autoimmunity by eliminating self-reactive T-cells. While mTECs produce self-antigens in an autonomous manner, DCs acquire them from mTECs via cooperative antigen transfer (CAT). Our recent data showed that preferential pairing occurs between distinct subsets of mTECs and DCs in CAT, providing a rationale for the existence of molecular determinants which control such pairing and the outcome of central tolerance. Here, we compared the transcriptomes of CAT-experienced and -inexperienced DCs and identified Claudin 1 as a molecule involved in CAT-coupled type 1 DC (DC1) maturation. By mapping thymic DC1 heterogeneity, we identified their early and late maturation states. DC1-specific ablation of Claudin 1 led to a reduction in CAT-experienced late mature DC1s and hampered DC1 maturation. These phenotypes correlated with the displacement of DC1s from the vicinity of mTECs. This translated into impaired Treg selection and clonal deletion of TRA-specific T-cells manifested via a break in tolerance and symptoms of multi-organ autoimmunity. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance. One Sentence SummaryThe expression of Claudin 1 on type 1 dendritic cells regulates their proximity to mTECs, which is required for effective antigen transfer coupled with DC1 maturation and establishment of T-cell tolerance.

immunology↗

bioRxiv2021

A model of preferential pairing between epithelial and dendritic cells in thymic antigen transfer

Medullary thymic epithelial cells (mTECs) which produce and present self-antigens are essential for the establishment of central tolerance. Since mTEC numbers are limited, their function is complemented by thymic dendritic cells (DCs), which transfer mTEC-produced self-antigens via cooperative antigen transfer (CAT). While CAT is required for effective T cell selection, many aspects remain enigmatic. Given the recently described heterogeneity of mTECs and DCs, it is unclear whether the antigen acquisition from a particular TEC subset is mediated by preferential pairing with specific subset of DCs. Using several relevant Cre-based mouse models controlling the expression of fluorescent proteins, we found that in regards to CAT, each subset of thymic DCs preferentially targets distinct mTEC subset(s) and importantly, XCR1+ activated DCs represented the most potent subset in CAT. Interestingly, one thymic DC can acquire antigen repetitively and of these, monocyte-derived DCs (moDC) were determined to be the most efficient in repetitive CAT. moDCs also represented the most potent DC subset in the acquisition of antigen from other DCs. These findings suggest a preferential pairing model for the distribution of mTEC-derived antigens among distinct populations of thymic DCs.

immunology↗