Proximity matters: Claudin-1 as an unexpected guardian of central tolerance

The images show the spatial arrangement of mTEC cells (green) and DC1 dendritic cells (red) in the mouse thymus. The 3D reconstruction was generated using light-sheet microscopy, which enables imaging of entire optically cleared tissues—in this case, the mouse thymus. Credit: Charles University

Scientists from the Institute of Molecular Genetics of the Czech Academy of Sciences, in collaboration with the Faculty of Science at Charles University, have uncovered a completely new role for the protein Claudin-1 in the immune system. The study is published in the Journal of Experimental Medicine.

The paper’s first author is Jiří Březina, and co-authors include Matouš Vobořil, Jan Dobeš, Jan Pačes, and Jan Černý. The corresponding author is Dominik Filipp.

The name claudin derives from the Latin claudere—”to close”—and refers to a family of proteins known as key structural components of tight junctions. These junctions literally seal the space between epithelial cells and create a physical barrier that prevents the uncontrolled passage of molecules and cells. A familiar example is the tight junction network lining the gut, which keeps digestive contents from leaking into the body.

Claudin-1’s unexpected immune function

The work now reveals that one of these molecules, Claudin-1, governs something far more delicate than sealing epithelial sheets: it helps determine how the immune system distinguishes self from non-self. The team discovered that Claudin-1—usually considered a hallmark epithelial protein—plays a crucial role in an unexpected cell type: type 1 dendritic cells (DC1). These cells are essential for establishing central tolerance in the thymus, the process that prevents autoimmune disease by eliminating T lymphocytes that react against the body’s own tissues.

Claudin 1 is upregulated in CAT-experienced DC1s. Credit: Journal of Experimental Medicine (2026). DOI: 10.1084/jem.20250970

The study dissects an underexplored mechanism within cooperative antigen transfer (CAT) between medullary thymic epithelial cells (mTEC) and DC1. mTEC produce a wide spectrum of tissue-restricted antigens and pass them to DC1, which then present them to developing T cells during their selection. For tolerance to be established properly, DC1 must remain in very close physical contact with specific mTEC subsets—particularly those expressing Aire and producing tissue-restricted antigens (TRA).

These TRAs enable the thymus to eliminate T cells that could later attack the body and cause autoimmune pathology. This interaction is also key for generating regulatory T cells, which restrain immune responses; their absence dramatically increases the risk of autoimmune disorders.

Here, Claudin-1 takes center stage. The study demonstrates that Claudin-1 enables precise docking of DC1 onto the mTEC network, likely through interactions with Claudin-3, which is abundantly expressed on Aire+ mTEC. When Claudin-1 is absent in DC1, the cells physically “drift” away from mTEC, fail to acquire sufficient antigen, do not fully mature, and present antigens poorly.

As a result, the entire system of central tolerance collapses—including defective regulatory T-cell development and failure to delete autoreactive T-cell clones. Mice lacking Claudin-1 in DC1 exhibit widespread multi-organ autoimmunity, develop autoantibodies, and have markedly shortened lifespans.

This discovery highlights a remarkable “moonlighting” function of a well-known molecule. Claudin-1 has been studied for decades as a structural component of epithelial tight junctions. The present work shows that it also exerts a completely distinct role in immune cells, positioning it as one of the most surprising new players in modern immunology. The study raises the intriguing possibility that other claudin family members may also have alternative functions outside classical epithelial biology.

Importance for autoimmune diseases

Autoimmune diseases are among the fastest-growing medical diagnoses worldwide. Understanding how the immune system establishes tolerance already in the thymus is essential for deciphering the causes of autoimmunity, developing targeted therapies, optimizing cancer immunotherapy and potentially engineering T-cell development in vitro.

This study introduces a wholly new concept: that the spatial positioning of DC1 relative to mTEC—and thus the architecture of the thymus itself—is controlled by molecules traditionally associated with epithelial biology. By doing so, it bridges two fields that historically rarely intersected: cell adhesion biology and central tolerance. The work opens new avenues for exploring the cellular and molecular mechanisms underlying autoimmune disease.

The thymus hosts more ‘cellular teachers’ than we thought, study finds