The thymus is a primary lymphoid organ of the immune system, situated mainly behind the breastbone in the upper chest. It provides the specialized environment in which T cells develop from blood-forming precursors into mature lymphocytes. Its central functions are to generate a diverse T-cell population for adaptive immunity and to establish central immune tolerance, which limits responses against the body’s own tissues. The thymus is particularly active early in life and undergoes progressive structural and functional changes with age. (ncbi.nlm.nih.gov)
Location and structure
The human thymus normally consists of two lobes in the anterior and superior portions of the mediastinum, the central compartment between the lungs. It lies behind the sternum and in front of the heart and major blood vessels; its upper portions may extend toward the neck. A connective-tissue capsule surrounds the organ, with inward partitions dividing its tissue into lobules. Each lobule contains an outer cortex and an inner medulla, although medullary tissue remains continuous between neighboring lobules. (my.clevelandclinic.org)
The cortex contains densely packed immature T cells, called thymocytes, supported by thymic epithelial cells and other stromal and immune cells. The medulla contains fewer thymocytes and a more conspicuous epithelial network, together with dendritic cells and other antigen-presenting cells. A characteristic feature of the human medulla is the presence of Hassall’s corpuscles, rounded groups of concentrically arranged epithelial cells. These structures participate in local signaling; experimental work has demonstrated their ability to influence dendritic-cell-mediated regulatory T-cell development. (pmc.ncbi.nlm.nih.gov)
Unlike secondary lymphoid organs, such as lymph nodes, the thymus is primarily a site of lymphocyte development rather than a site where mature lymphocytes initiate responses to invading microorganisms. Its organization brings developing cells into contact with different supporting cell populations at successive maturation stages. (ncbi.nlm.nih.gov)
T-cell development
T-cell precursors originate from blood-forming cells in the bone marrow and enter the thymus through the circulation. The thymus supplies signals that support their survival, proliferation, and differentiation. As they move through its compartments, developing cells assemble the genes encoding their T-cell receptors through V(D)J recombination. This rearrangement generates receptors with many different recognition properties. (ncbi.nlm.nih.gov)
Most conventional T cells carry receptors composed of alpha and beta chains. During development, their precursors progress from a double-negative stage, lacking both CD4 and CD8 surface co-receptors, to a double-positive stage expressing both. Cells that complete selection generally become single-positive, retaining either CD4 or CD8. CD4 T cells usually recognize peptides presented by class II major histocompatibility complex molecules, whereas CD8 T cells recognize peptides presented by class I molecules. (ncbi.nlm.nih.gov)
Only a minority of developing thymocytes leave as mature T cells. Many die because they fail to assemble a functional receptor or do not receive appropriate survival signals. Mature cells enter the bloodstream and populate peripheral lymphoid tissues, initially as naïve T cells that have not yet encountered the foreign antigens capable of activating them. (ncbi.nlm.nih.gov)
Selection and immune tolerance
Positive selection, principally associated with cortical epithelial cells, preserves thymocytes whose receptors can recognize self-MHC molecules bearing peptides. Cells unable to make a sufficiently productive interaction fail to receive survival signals and undergo apoptosis, or programmed cell death. Positive selection establishes the MHC recognition needed for conventional T cells to function after leaving the thymus. (ncbi.nlm.nih.gov)
Negative selection removes many thymocytes that react too strongly to self-peptide–MHC complexes. This process, also called clonal deletion, occurs at several developmental stages and is particularly important in the medulla. Medullary epithelial cells and other antigen-presenting cells expose developing T cells to a broad range of self-antigens. (ncbi.nlm.nih.gov)
The autoimmune regulator protein, AIRE, helps medullary epithelial cells express numerous tissue-restricted antigens, including molecules ordinarily associated with organs outside the thymus. Their presentation allows developing T cells to be tested against a wider representation of the body’s tissues. Defects in this mechanism can impair self-tolerance. (pmc.ncbi.nlm.nih.gov)
Not every thymocyte recognizing self-antigens is deleted. Some develop into regulatory T cells, which help suppress inappropriate immune responses. Thymic selection nevertheless does not eliminate every potentially self-reactive cell. Peripheral immune tolerance supplies additional controls after T cells leave the organ, complementing thymic mechanisms that constrain autoimmunity. (nature.com)
Changes across the lifespan
The thymus supports T-cell development before birth and is prominent during childhood. With age, it undergoes thymic involution: functional thymic tissue diminishes, its architecture changes, and fat occupies an increasing proportion of the organ. This process becomes especially evident after puberty and is associated with reduced production of new naïve T cells. Involution does not mean that thymic activity stops abruptly or that all thymic tissue disappears. (my.clevelandclinic.org)
The mature peripheral T-cell population can persist through cellular longevity and proliferation outside the thymus. Consequently, declining thymic output differs from immediate loss of T-cell immunity, although the thymus remains an important source of newly generated cells. (pmc.ncbi.nlm.nih.gov)
Clinical significance
Congenital absence or severe underdevelopment of the thymus can cause profound T-cell immunodeficiency. Complete DiGeorge syndrome is one setting in which thymic absence occurs. DiGeorge-associated developmental abnormalities frequently belong to the spectrum of 22q11.2 deletion syndrome, whose manifestations and immune impairment vary considerably between individuals. (nejm.org)
Thymoma and thymic carcinoma are rare tumors arising from thymic epithelial cells. They differ in their microscopic characteristics and clinical behavior. Thymoma is associated with several immune disorders, particularly myasthenia gravis, an autoimmune disease affecting neuromuscular transmission. Other recognized associations include Good syndrome and pure red-cell aplasia. Some thymic tumors are discovered incidentally during chest imaging rather than through symptoms attributable to the thymus. (cancer.gov)