Thymus

The thymus is a small, bilobed organ that is part of the lymphatic and immune systems. It plays a vital role in the development and maturation of T-lymphocytes (T cells), which are essential for the adaptive immune system. The thymus is larger and more active during childhood and adolescence, gradually shrinking and becoming less functional as a person ages, a process known as involution.

Location

The thymus is located in the mediastinum, the central compartment of the thoracic cavity. It sits behind the sternum, specifically in the anterior superior mediastinum, and lies in front of the heart and major blood vessels such as the aorta. The thymus extends from the lower part of the neck to the upper part of the chest.

Structure and Anatomy

The thymus is a bilobed organ that plays a crucial role in the development of the immune system. Structurally, it is composed of two distinct lobes, each subdivided into lobules, and it is made up of specialized epithelial cells and lymphoid tissue. The thymus is most active during childhood and adolescence, and it undergoes significant changes with age. Below is a detailed description of the anatomy of the thymus:

External Structure

The thymus has a distinct appearance characterized by its lobulated structure. It is soft and pinkish-gray in color and surrounded by a thin capsule of connective tissue.

Lobes

The thymus consists of two lobes, the right lobe and the left lobe, which are connected by a thin layer of tissue in the midline. These lobes are asymmetrical, and together they form the overall shape of the thymus.

Capsule

The thymus is surrounded by a thin, fibrous capsule, which provides structural support and protection. The capsule extends inward to form trabeculae, or septa, which divide the thymic lobes into smaller lobules.

Lobules

The lobules are the structural units of the thymus and are roughly 0.5 to 2 millimeters in diameter. Each lobule consists of an outer cortex and an inner medulla, with distinct cellular composition and architecture.

Internal Structure

The internal structure of the thymus is divided into two main regions: the cortex and the medulla. These regions have different functions and cellular compositions.

Cortex

• The cortex is the outermost layer of the thymic lobules. It is densely packed with immature T lymphocytes (thymocytes) and is the site of early T cell development.
• The cortex is supported by a network of epithelial reticular cells, which provide structural support and secrete hormones that regulate the maturation of thymocytes.
• Macrophages are also present in the cortex to remove apoptotic thymocytes that fail to properly mature.

Medulla

• The medulla forms the inner region of each lobule and is less densely populated with thymocytes compared to the cortex. The medulla contains more mature T cells that are nearing the end of their developmental process.
• The epithelial reticular cells in the medulla are larger and more loosely organized than those in the cortex. They form the Hassall’s corpuscles, which are concentric structures of epithelial cells. The function of Hassall’s corpuscles is not entirely clear, but they are thought to play a role in the maturation of regulatory T cells.

Hassall’s Corpuscles

• Hassall’s corpuscles are unique to the thymic medulla and are composed of concentric layers of epithelial cells that become keratinized at the center. These structures are more prominent in older individuals and increase in number with age.
• While their exact function is not fully understood, Hassall's corpuscles are believed to be involved in the elimination of apoptotic thymocytes and the regulation of immune responses.

Vascular Supply

The thymus is richly vascularized, with blood vessels entering and leaving the organ to supply it with nutrients and oxygen, as well as to carry away mature T cells for circulation.

Arterial Supply

• The thymus receives its blood supply from the internal thoracic arteries, which are branches of the subclavian arteries. Additional blood supply comes from branches of the inferior thyroid arteries, anterior intercostal arteries, and pericardiacophrenic arteries.
• Small arteries penetrate the thymic capsule and form a network of capillaries that supply the cortex and medulla with blood.

Venous Drainage

The veins of the thymus drain into the left brachiocephalic vein, the internal thoracic vein, and the inferior thyroid veins. These veins carry deoxygenated blood away from the thymus.

Blood-Thymus Barrier

The blood-thymus barrier is a specialized structure that protects developing thymocytes in the cortex from exposure to antigens in the bloodstream. This barrier is composed of epithelial cells, endothelial cells, and macrophages that form a protective layer around the cortical capillaries.

Lymphatic Drainage

The thymus plays a key role in the immune system, and its lymphatic drainage ensures that immune cells are transported efficiently throughout the body.

Afferent and Efferent Lymphatic Vessels

• The thymus does not have afferent lymphatic vessels (vessels that bring lymph into the organ), meaning that it does not receive lymph from other tissues.
• The thymus does have efferent lymphatic vessels that drain lymph from the organ. These vessels carry mature T lymphocytes from the thymus to the bloodstream and other parts of the lymphatic system. The lymph from the thymus drains into the parasternal, brachiocephalic, and tracheobronchial lymph nodes.

Nerve Supply

The thymus receives innervation from the autonomic nervous system, which helps regulate its functions.

Sympathetic Innervation

The sympathetic nervous system provides innervation to the thymus via branches of the cervical sympathetic ganglia. Sympathetic fibers influence the activity of the thymic epithelial cells and the maturation of thymocytes.

Parasympathetic Innervation

The parasympathetic innervation of the thymus is provided by the vagus nerve (cranial nerve X). Although its role in thymic function is not fully understood, it likely contributes to the regulation of immune processes within the organ.

Age-Related Changes (Involution)

The thymus undergoes a process of involution as an individual ages, meaning that it gradually shrinks and becomes less active over time. This process involves a reduction in the size of the thymus and the replacement of functional tissue with fatty tissue.

Childhood Thymus

In infants and young children, the thymus is relatively large and highly active. It is essential for the development of the immune system during early life.

Thymic Involution

Starting around puberty, the thymus begins to shrink and undergoes involution, a process in which the functional lymphoid tissue is gradually replaced by adipose tissue (fat). The involuted thymus retains some functionality, but its capacity to produce new T cells diminishes with age.

Adult Thymus

In adults, the thymus is much smaller and consists largely of fatty tissue, though it still retains some areas of functional thymic tissue. Even in later life, the thymus continues to contribute to immune function, although at a much-reduced rate.

Function

The thymus plays a crucial role in the development and function of the immune system, particularly in the maturation of T-lymphocytes (T cells), which are essential for the body's adaptive immune response. It is responsible for the development, education, and selection of T cells, ensuring that only functional and non-self-reactive T cells enter circulation. Below is a detailed description of the various functions of the thymus.

T Cell Maturation

The primary function of the thymus is to support the maturation of T-lymphocytes (T cells), which are critical for the adaptive immune system. T cells originate in the bone marrow as immature cells and migrate to the thymus for further development.

Thymocyte Development

• Immature T cells, called thymocytes, enter the thymus from the bone marrow. These thymocytes first enter the cortex of the thymus, where they begin their development by undergoing several stages of differentiation.
• In the cortex, thymocytes proliferate and express specific surface receptors, such as the T cell receptor (TCR), which enables them to recognize antigens.

Positive Selection (MHC Restriction)

• In the thymic cortex, thymocytes undergo positive selection, a process that ensures they can recognize antigens in the context of major histocompatibility complex (MHC) molecules. Thymocytes that bind appropriately to MHC molecules on epithelial cells are selected to survive, while those that do not interact with MHC are eliminated by apoptosis.
• This step ensures that T cells can recognize foreign antigens presented by MHC molecules on the surface of antigen-presenting cells.

T Cell Selection (Central Tolerance)

The thymus plays a critical role in preventing autoimmunity by ensuring that self-reactive T cells, which could attack the body’s own tissues, are eliminated. This process is known as central tolerance.^[7]

Negative Selection

• In the medulla of the thymus, thymocytes that have passed positive selection undergo negative selection. This process eliminates T cells that bind too strongly to self-antigens presented by medullary thymic epithelial cells (mTECs) or dendritic cells.
• Thymocytes that strongly recognize self-antigens undergo apoptosis, ensuring that self-reactive T cells do not enter the bloodstream. This mechanism is essential for maintaining self-tolerance and preventing autoimmune diseases.

Role of AIRE Protein

The autoimmune regulator (AIRE) protein, expressed by medullary thymic epithelial cells, is essential for the presentation of a wide variety of self-antigens to developing thymocytes. AIRE allows for the expression of tissue-specific antigens in the thymus, ensuring that self-reactive T cells are eliminated even if they recognize antigens normally expressed in distant tissues (e.g., the pancreas or thyroid).

Production of Functional T Cells

The thymus is responsible for producing fully functional T cells that can recognize foreign pathogens and mount an immune response.^[5] This process is crucial for the development of both helper T cells and cytotoxic T cells.

Helper T Cells (CD4+ T Cells)

Helper T cells express the CD4 surface marker and are essential for coordinating the immune response. After maturation in the thymus, CD4+ T cells assist other immune cells, such as B cells and cytotoxic T cells, by secreting cytokines that regulate immune activity.

Cytotoxic T Cells (CD8+ T Cells)

Cytotoxic T cells express the CD8 surface marker and are responsible for directly attacking and destroying infected or cancerous cells. These cells recognize antigens presented by MHC class I molecules and play a key role in defending the body against intracellular pathogens like viruses.

Regulatory T Cells (Tregs)

A subset of thymocytes differentiate into regulatory T cells (Tregs), which are essential for maintaining immune tolerance and preventing excessive immune reactions.^[3] Tregs suppress the activity of other immune cells, helping to prevent autoimmune responses.

Central Role in Immune Tolerance

The thymus plays a pivotal role in developing immune tolerance, which prevents the immune system from attacking the body’s own tissues.

Development of Self-Tolerance

Through positive and negative selection processes, the thymus ensures that self-reactive T cells are eliminated, and only T cells capable of recognizing foreign antigens without attacking self-tissues are released into circulation. This is crucial for preventing autoimmune diseases.

Regulatory T Cell Generation

The thymus generates regulatory T cells (Tregs), which are critical for maintaining immune tolerance.^[1] Tregs suppress the activation of self-reactive T cells that may escape the thymus and prevent excessive or inappropriate immune responses.

T Cell Release into Circulation

Once T cells have undergone maturation and selection in the thymus, they are released into the bloodstream, where they travel to secondary lymphoid organs, such as lymph nodes and the spleen, to perform their immune functions.

Efferent Lymphatic Drainage

The thymus contains efferent lymphatic vessels, which transport mature T cells from the thymus to other parts of the immune system. These T cells enter the peripheral circulation and populate the secondary lymphoid tissues.

Circulation to Lymphoid Organs

After leaving the thymus, T cells travel through the bloodstream to lymph nodes, the spleen, and other lymphoid organs.^[8] These organs are sites where T cells encounter foreign antigens, become activated, and initiate immune responses.

Involution with Age

As a person ages, the thymus gradually decreases in size and function in a process known as involution. Although the thymus is most active during childhood, it continues to play a role in immune regulation throughout life.

Thymic Involution

During thymic involution, the thymus shrinks and becomes infiltrated with fat, leading to a reduction in its ability to produce new T cells. However, residual thymic tissue continues to function and contribute to immune regulation, albeit at a reduced capacity.

Compensatory Immune Mechanisms

Although the thymus decreases in size and activity with age, the immune system compensates by maintaining populations of memory T cells that were produced during earlier stages of life.^[6] These memory T cells can respond to previously encountered pathogens, even as the production of new T cells declines.

Production of Thymic Hormones

The thymus produces several hormones that regulate the development and maturation of T cells.

Thymosin

Thymosin is a hormone secreted by thymic epithelial cells that stimulates the maturation of thymocytes into functional T cells. It plays a critical role in promoting T cell differentiation and immune competence.

Thymopoietin and Thymulin

Thymopoietin and thymulin are other thymic hormones involved in the differentiation and proliferation of T cells. These hormones regulate the expression of surface receptors on developing T cells, guiding their maturation process.^[4]

Role in Early Development of the Immune System

The thymus is essential for the proper development of the immune system in early life. It provides a specialized environment for the maturation of T cells, which are critical for adaptive immunity.

Fetal Immune Development

During fetal development, the thymus is one of the first lymphoid organs to develop, and it plays a key role in establishing the immune system. It ensures the production of functional T cells before birth, allowing the newborn to respond to pathogens after birth.

Postnatal Immune Development

In the early years of life, the thymus is highly active, producing large numbers of T cells to populate the peripheral immune system.^[2] This ensures that the body is equipped to handle various pathogens during childhood, a time when the immune system is constantly challenged.

Clinical Significance

The thymus is crucial for the development of a healthy immune system, particularly in early life, as it is responsible for the maturation of T cells, which are essential for adaptive immunity. Thymic dysfunction or disorders can have significant consequences. For instance, DiGeorge syndrome, a genetic disorder, leads to poor thymic development and results in immunodeficiency due to a lack of functional T cells. Thymomas and thymic carcinomas, which are tumors of the thymus, can also impair immune function and are often associated with autoimmune conditions such as myasthenia gravis. As the thymus undergoes involution with age, its ability to produce new T cells decreases, which may contribute to weakened immune function in the elderly, making them more susceptible to infections and certain cancers. Thymic abnormalities can also affect immune tolerance, increasing the risk of autoimmune diseases. Understanding thymic function is critical in the context of immunodeficiencies, cancer, and autoimmune disorders.