The Thymus

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, Thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

The thymus is made up of immature T cells called thymocytes, as well as lining cells called epithelial cells which help the thymocytes develop. T cells that successfully develop react appropriately with MHC immune receptors of the body (called positive selection,) and not against proteins of the body, (called negative selection).

The thymus is largest and most active during the neonatal and pre-adolescent periods. By the early teens, the thymus begins to decrease in size and activity and the tissue of the thymus is gradually replaced by fatty tissue. Nevertheless, some T cell development continues throughout adult life.

Structure

The thymus is an organ that sits beneath the sternum in the upper front part of the chest, stretching upwards towards the neck. In children, the thymus is pinkish-gray, soft, and lobulated on its surfaces. At birth it is about 4–6 cm long, 2.5–5 cm wide, and about 1 cm thick. It increases in size until puberty, where it may have a size of about 40–50 g, following which it decreases in size in a process known as involution.

The thymus is made up of two lobes that meet in the upper midline, and stretch from below the thyroid in the neck to as low as the cartilage of the fourth rib. The lobes are covered by a capsule. The thymus lies beneath the sternum, rests on the pericardium, and is separated from the  aortic arch and great vessels by a layer of fascia. The left brachiocephalic vein may even be embedded within the thymus. In the neck, it lies on the front and sides of the trachea, behind the sternohyoid and sternothyroid muscles

Functions of the Thymus

T cell maturation

The thymus facilitates the maturation of T cells, an important part of the immune system providing cell-mediated immunity. T cells begin as hematopoietic precursors from the bone-marrow, and migrate to the thymus, where they are referred to as thymocytes. In the thymus they undergo a process of maturation, which involves ensuring the cells react against antigens (“positive selection”), but that they do not react against antigens found on body tissue (“negative selection”). Once mature, T cells emigrate from the thymus to provide vital functions in the immune system.

Each T cell has a distinct T cell receptor, suited to a specific substance, called an antigen. Most T cell receptors bind to the major histocompatibility complex on cells of the body. The MHC presents an antigen to the T cell receptor, which becomes active if this matches the specific T cell receptor. In order to be properly functional, a mature T cell needs to be able to bind to the MHC molecule (“positive selection”), and not to react against antigens that are actually from the tissues of body (“negative selection”).

Positive selection occurs in the cortex and negative selection occurs in the medulla of the thymus. After this process T cells that have survived leave the thymus, regulated by sphingosine-1-phosphate. Further maturation occurs in the peripheral circulation. Some of this is because of hormones and cytokines secreted by cells within the thymus, including thymulin, thymopoietin, and thymosins.

Positive selection

T cells have distinct T cell receptors. These distinct receptors are formed by process of V(D)J recombination gene rearrangement stimulated by RAG1 and RAG2 genes. This process is error-prone, and some thymocytes fail to make functional T-cell receptors, whereas other thymocytes make T-cell receptors that are autoreactive. If a functional T cell receptor is formed, the thymocyte will begin to express simultaneously the cell surface proteins CD4 and CD8.

The survival and nature of the T cell then depends on its interaction with surrounding thymic epithelial cells. Here, the T cell receptor interacts with the MHC molecules on the surface of epithelial cells. A T cell with a receptor that doesn’t react, or reacts weakly will die by apoptosis. A T cell that does react will survive and proliferate. A mature T cell expresses only CD4 or CD8, but not both. This depends on the strength of binding between the TCR and MHC class 1 or class 2. A T cell receptor that binds mostly to MHC class I tends to produce a mature “cytotoxic” CD8 positive T cell; a T cell receptor that binds mostly to MHC class II tends to produces a CD4 positive T cell.

Negative selection

T cells that attack the body’s own proteins are eliminated in the thymus, called “negative selection”. Epithelial cells in the medulla and dendritic cells in the thymus express major proteins from elsewhere in the body. The gene that stimulates this is AIRE. Thymocytes that react strongly to self antigens do not survive, and die by apoptosis. Some CD4 positive T cells exposed to self antigens persist as T regulatory cells