# Claudin 1–mediated positioning of DC1 to mTECs is essential for maintenance of central tolerance

## TL;DR

This study shows that Claudin 1 helps position immune cells in the thymus, which is crucial for preventing autoimmune diseases.

## Contribution

The study identifies Claudin 1 as a novel regulator of immune tolerance through its role in positioning dendritic cells near thymic epithelial cells.

## Key findings

- DC1-specific ablation of Claudin 1 leads to impaired antigen transfer and reduced DC1 maturation.
- Loss of Claudin 1 results in impaired Treg selection and increased autoimmunity.
- Claudin 1 is essential for maintaining immune tolerance by regulating DC1 positioning and function.

## Abstract

Březina et al. demonstrate that Claudin 1 enables thymic type 1 dendritic cells to localize within proximity to medullary thymic epithelial cells. This spatial arrangement supports maturation and tolerogenic function of type 1 dendritic cells, thus preventing disruptions in T-cell tolerance.

Central tolerance, which relies on the presentation of self-antigens by mTECs and DCs, prevents autoimmunity by eliminating self-reactive T cells. While mTECs produce self-antigens autonomously, DCs acquire them from mTECs via cooperative antigen transfer (CAT). We previously showed that mTEC and DC subsets exhibit preferential pairing in CAT, providing a rationale for the existence of molecular determinants underpinning this pairing and its outcome. Here, we compared the transcriptomes of CAT-experienced and CAT-inexperienced DCs and identified Claudin 1 as a molecule involved in CAT and type 1 DC (DC1) maturation. DC1-specific ablation of Claudin 1 resulted in decreased CAT to late mature DC1s and dramatically diminished DC1 maturation. These phenotypes correlated with the displacement of DC1s from mTECs and their decreased expression of MHCII pathway genes. This translated into impaired Treg selection and clonal deletion, ultimately manifesting in symptoms of multiorgan autoimmunity and shortened lifespan. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance.