What is the function of the thymus?

What is the Thymus?

The thymus is a primary lymphoid organ that generates immunocompetent T lymphocytes through a process of selection and maturation, establishing central tolerance by eliminating self-reactive T cells while producing naive T cells capable of recognizing diverse pathogens. 1, 2, 3

Core Function: T Cell Development and Selection

The thymus serves as the essential site where hematopoietic progenitor cells from bone marrow differentiate into mature T lymphocytes through a highly regulated process 2, 3, 4:

• Positive and negative selection occurs within the thymic cortex and medulla, where developing thymocytes (immature T cells) are tested for their ability to recognize self-MHC molecules with appropriate affinity 1, 2
• Cells with high affinity for self-antigens are eliminated through negative selection (clonal deletion), preventing autoimmunity 1, 2
• Cells with low affinity are also eliminated through lack of positive selection, ensuring only functional T cells survive 1
• Only T cells with intermediate affinity for self-MHC survive and exit the thymus as naive T cells capable of recognizing foreign antigens 2, 3

Central Tolerance Mechanism

The thymus establishes central tolerance through a sophisticated molecular system 1:

• The autoimmune regulator (AIRE) gene/protein controls the presentation of multiple self-peptides by thymic MHC proteins, allowing developing T cells to encounter a broad representation of self-antigens 1
• Regulatory T cells (Tregs) are generated as a critical subset—these FOXP3+ CD4+ CD25+ cells have high-affinity receptors for self-MHC:peptide complexes and function to suppress self-reactive T cells that escape negative selection 1, 5
• These Tregs mature in the thymus as positively selected thymocytes receiving slightly weaker signals than those eliminated by negative selection 5

Temporal Activity and Age-Related Changes

Thymic function varies dramatically across the lifespan 1, 6, 7:

• Peak activity occurs at 3-6 months of age with maximum numbers of total thymocytes and high percentages of double-positive cells 1
• The thymus remains functional well into the sixth decade of life, contributing naive T cells throughout adulthood 6
• Age-related involution leads to decreased T cell development, reduced naive T cell emigration, increased proportion of memory T cells, and restricted T cell receptor repertoire 7
• Thymic output can be measured using T cell receptor excision circles (TRECs) and the percentage of naive T lymphocytes 1

Clinical Significance: Distinguishing Normal from Pathological States

Understanding thymic function is critical for diagnosing immunodeficiency 8, 1:

Complete Athymia (Life-Threatening)

• TRECs are negligible and less than 5% of T cells display naive phenotype, reflecting absent thymic output 8, 1
• These patients require thymus transplantation as definitive treatment, as they lack the thymic niche necessary for T cell development 8
• Survival without treatment is not possible due to severe combined immunodeficiency 8

Thymic Hypoplasia (Partial Function)

• Reduced but not absent numbers of naive T cells and TRECs at all ages, indicating persistently reduced but present thymic function 1
• These patients may require only supportive care rather than thymus transplantation 8

Structural Organization

The thymus functions as a complex chimeric organ 6, 4:

• Central thymic epithelial space provides the microenvironment for T cell development 6
• Peripheral perivascular space allows entry of bone marrow progenitors and exit of mature T cells 6
• Cortical and medullary regions provide spatially regulated checkpoints for T cell maturation and selection 3
• Normal architecture includes Hassall's corpuscles and distinct corticomedullary organization, which are absent in complete athymia 1

Clinical Pitfalls to Avoid

When assessing thymic function, recognize these confounding factors 9:

• Low total lymphocyte counts can be masked by elevated B-cell or NK-cell numbers, or by oligoclonal T-lymphocyte expansions in immunodeficiency states 9
• Maternal T-lymphocyte engraftment can paradoxically elevate T-lymphocyte counts in athymic patients despite severe immunodeficiency 9
• Inflammation, infection, and sepsis cause lymphopenia independent of thymic function 9