What is the function of the thymus?

Function of the Thymus

The thymus is the primary lymphoid organ responsible for T cell development and maturation, playing a crucial role in establishing adaptive immunity by generating functionally distinct T lymphocyte populations that are essential for protection against infections, immune disorders, and cancer. 1, 2

Primary Functions

• The thymus serves as the site for T lymphocyte development, where immature T cell precursors undergo maturation and selection processes to become functional T cells 1
• It establishes central tolerance through elimination of self-reactive T cells and generation of regulatory T cells (Tregs), preventing autoimmune responses 3
• The thymus exports naïve T cells to the periphery with the potential to recognize diverse pathogens, maintaining a broad T cell receptor (TCR) repertoire 2
• It contributes to immune system homeostasis by balancing the production of different T cell subpopulations, including conventional CD4+ and CD8+ T cells, regulatory T cells, natural killer T cells, and γδT cells 1

Structural Components and Organization

• The thymus has a complex chimeric structure comprised of:

  • Thymic epithelial cells (TECs) that form the primary stromal framework and guide T cell development 4
  • Cortical regions where positive selection of T cells occurs 2
  • Medullary regions where negative selection eliminates self-reactive T cells 4
  • Perivascular spaces that contain peripheral components 5

• Thymic epithelial cells are further divided into:

  • Cortical TECs involved in positive selection of developing T lymphocytes 4
  • Medullary TECs responsible for negative selection and establishment of self-tolerance 4

Key Mechanisms of Action

• The thymus facilitates T cell receptor (TCR) rearrangement and selection processes to generate a diverse T cell repertoire 2
• It enables promiscuous gene expression (pGE) of tissue-restricted antigens by medullary thymic epithelial cells, controlled by regulatory factors such as Autoimmune Regulator (Aire) and Fezf2 4
• Regulatory T cells develop in the thymus as a subset of positively selected thymocytes that receive slightly weaker signals than those eliminated by negative selection 3
• Treg T cell receptors have high affinity for self-MHC:peptide complexes, allowing them to recognize self-antigens and maintain immune tolerance 3

Clinical Significance

• Congenital thymic defects (athymia) result in severe T cell immunodeficiency with life-threatening consequences, requiring thymus transplantation for survival 6

• Thymic output naturally declines with age (thymic involution), leading to:

  • Decreased naïve T cell production 7
  • Restricted T cell receptor diversity 7
  • Increased susceptibility to infections 7
  • Higher risk for autoimmune disorders and cancer 7

• Thymic function is critical for immune reconstitution after:

  • Hematopoietic stem cell transplantation 5
  • HIV-1 infection 5
  • Other conditions requiring immune system regeneration 5

Diagnostic Considerations

• Thymic output can be assessed by measuring:

  • T cell receptor excision circles (TRECs) 6
  • Percentage of naïve T cells expressing CD31 (recent thymic emigrants) 6
  • T cell counts and subpopulations 6

• Complete athymia is characterized by:

  • Low total lymphocyte counts (though they can be normal due to B or NK cell expansion) 6
  • Negligible TRECs 6
  • Less than 5% of T lymphocytes displaying a naïve phenotype 6

Treatment Implications

• Thymus transplantation is the recommended first-line treatment for congenital athymia, providing durable T-lymphocyte immunity and improved quality of life 6
• Therapeutic modulation of thymus-derived regulatory T cells represents a promising approach for treating selected disorders and preventing allograft rejection 3
• Strategies to mitigate thymic involution may help maintain immune function in elderly and immunocompromised individuals 7