Central tolerance articles from across Nature Portfolio

This Review summarizes how the processes of thymic selection together ensure that the T cell repertoire is fully functional and safe. In the thymus, T cell receptor signal strength is integrated with distinct stromal cues to result in positive or negative selection of thymocytes or the generation of regulatory cells.

The thymus generates all T cells, including those that underly autoimmune diseases. Here, using deep sequencing, the authors profile human medullary thymic epithelial cells and establish a web portal to query their transcriptome, which may serve as a tool to help identify the drivers of autoimmunity.

The missense TLR7^Y264H gain-of-function genetic variation causes systemic lupus erythematosus in humans and mice.

T cells are selected in the thymus, through interaction with self-antigens, to remove autoreactive cells. Here the authors show that a specialized thymic dendritic cell subset juxtaposes to microvessels, requires CX₃CR1/CX₃CL1 for this positioning, and has processes extruding into the blood stream to sample soluble macromolecules and assist in T cell selection.

The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.

A paper in Nature reports a ‘Z-DNA-anchored’ model for the target specificity of the transcription factor AIRE, involving promoter poising at double-strand breaks.

Medullary thymic epithelial cells co-opt lineage-defining transcription factors to mimic numerous peripheral cell types and express their antigens against which maturing T cells can be tolerized.

Whether and how thymic tolerance to tissue-restricted antigens (TRA) could be achieved posed a conundrum until Klein and colleagues discovered that medullary thymic epithelial cells were capable of bursts of TRA expression.

Rémy Bosselut describes a 2001 paper by Jordan et al. showing that CD25⁺ regulatory T cells can be selected on self-peptides, which provided important insights into mechanisms of thymic tolerance.