Thymic Cell Development and Autoimmunity

The thymus is the central organ for T lymphocyte generation and self‐tolerance. Within its cortex and medulla, thymic epithelial cells (TECs) present peptide–major histocompatibility complexes that drive positive selection of useful T cells and negative selection of potentially autoreactive clones. Medullary TECs use the autoimmune regulator (AIRE) to express a diverse array of tissue‐restricted antigens, enforcing central tolerance and preventing autoimmunity. During life the thymus undergoes involution: a progressive shrinkage and remodelling that reduces naive T cell output and compromises self‐tolerance. Genetic defects in AIRE or other transcriptional regulators, age‐associated changes in TEC subsets and alterations in thymic stromal niches can all perturb central tolerance, permitting escape of autoreactive T cells and the development of systemic or organ‐specific autoimmune disorders.

Research from Nature Portfolio

Recent studies have applied single-cell and spatial transcriptomics to characterise age-associated epithelial changes that underlie impaired thymic regeneration. A novel subset of age-associated TECs (aaTECs) has been identified forming dense peri-medullary clusters devoid of thymocytes and exhibiting features of epithelial-to-mesenchymal transition. These aaTECs draw trophic signals away from functional TECs, correlate with downregulation of the key transcription factor FOXN1 and expand further after acute injury, thereby hampering thymic repair. This mechanistic insight into thymic involution highlights potential targets for immune-boosting therapies in older individuals and underscores the dynamic interplay between epithelial subpopulations and thymopoiesis.

Thymic Cell Development and Autoimmunity publication trend

The graph below shows the total number of articles in thymic cell development and autoimmunity across all publications each year (not limited to Nature Index journals).

Technical terms

Thymic epithelial cell (TEC): Specialized stromal cells forming cortical and medullary microenvironments that guide T cell maturation and tolerance induction.

Autoimmune regulator (AIRE): Transcription factor expressed in medullary TEC that drives ectopic expression of self-antigens for negative selection of autoreactive T cells.

Central tolerance: The process by which developing T cells that recognise self-antigens with high affinity are deleted in the thymus to prevent autoimmunity.

Promiscuous gene expression (PGE): The ectopic activation of tissue-restricted genes by medullary TEC to present a wide array of self-antigens during T cell selection.

Thymic involution: The age-associated shrinkage and functional decline of the thymus characterised by reduced thymopoiesis and structural remodelling.

Tissue-restricted antigen (TRA): Self-antigen normally expressed in specific peripheral tissues, ectopically displayed in the thymus for tolerance induction.

Age-associated TEC (aaTEC): A subpopulation of thymic epithelial cells that emerge with age and contribute to impaired thymic regeneration.

References

1. Age-related epithelial defects limit thymic function and regeneration. Nature Immunology (2024).
2. AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies. Cell (2016).
3. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Research (2014).
4. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. Journal of Clinical Investigation (2016).