thymus 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 to specific 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. thymusthymusexplanation of the thymus's functiondetailsprecursorthird pharyngeal pouchsystemlymphatic system, part of the immune systemlymphtracheobronchial, parasternalfunctionsupport the development of functional t cellsidentifierslatinthymusmeshd013950ta98a13.1.02.001ta25152fma9607anatomical terminology 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. abnormalities of the thymus can result in a decreased number of t cells and autoimmune diseases such as autoimmune polyendocrine syndrome type 1 and myasthenia gravis. these are often associated with cancer of the tissue of the thymus, called thymoma, or tissues arising from immature lymphocytes such as t cells, called lymphoma. removal of the thymus is called thymectomy. although the thymus has been identified as a part of the body since the time of the ancient greeks, it is only since the 1960s that the function of the thymus in the immune system has become clearer. structure the thymus is an organ that sits behind 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 located in the anterior mediastinum. it 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 behind 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. microanatomy the thymus consists of two lobes, merged in the middle, surrounded by a capsule that extends with blood vessels into the interior. the lobes consist of an outer cortex rich with cells and an inner less dense medulla. the lobes are divided into smaller lobules 0.5-2 mm diameter, between which extrude radiating insertions from the capsule along septa. the cortex is mainly made up of thymocytes and epithelial cells. the thymocytes, immature t cells, are supported by a network of the finely-branched epithelial reticular cells, which is continuous with a similar network in the medulla. this network forms an adventitia to the blood vessels, which enter the cortex via septa near the junction with the medulla. other cells are also present in the thymus, including macrophages, dendritic cells, and a small amount of b cells, neutrophils and eosinophils. in the medulla, the network of epithelial cells is coarser than in the cortex, and the lymphoid cells are relatively fewer in number. concentric, nest-like bodies called hassall's corpuscles (also called thymic corpuscles) are formed by aggregations of the medullary epithelial cells. these are concentric, layered whorls of epithelial cells that increase in number throughout life. they are the remains of the epithelial tubes, which grow out from the third pharyngeal pouches of the embryo to form the thymus. micrograph showing a lobule of the thymus. the cortex (deeper purple area) surrounds a less dense and lighter medulla. micrograph showing a hassall's corpuscle, found within the medulla of the thymus. blood and nerve supply the arteries supplying the thymus are branches of the internal thoracic, and inferior thyroid arteries, with branches from the superior thyroid artery sometimes seen. the branches reach the thymus and travel with the septa of the capsule into the area between the cortex and medulla, where they enter the thymus itself; or alternatively directly enter the capsule. the veins of the thymus, the thymic veins, end in the left brachiocephalic vein, internal thoracic vein, and in the inferior thyroid veins. sometimes the veins end directly in the superior vena cava. lymphatic vessels travel only away from the thymus, accompanying the arteries and veins. these drain into the brachiocephalic, tracheobronchial and parasternal lymph nodes. the nerves supplying the thymus arise from the vagus nerve and the cervical sympathetic chain. branches from the phrenic nerves reach the capsule of the thymus, but do not enter into the thymus itself. variation the two lobes differ slightly in size, with the left lobe usually higher than the right. thymic tissue may be found scattered on or around the gland, and occasionally within the thyroid. the thymus in children stretches variably upwards, at times to as high as the thyroid gland. development scheme showing development of branchial epithelial bodies from the thoracic cavity of the foetus. i, ii, iii, iv. branchial pouches. the thymocytes and the epithelium of the thymus have different developmental origins. the epithelium of the thymus develops first, appearing as two outgrowths, one on either side, of the third pharyngeal pouch. it sometimes also involves the fourth pharyngeal pouch. these extend outward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta. here the thymocytes and epithelium meet and join with connective tissue. the pharyngeal opening of each diverticulum is soon obliterated, but the neck of the flask persists for some time as a cellular cord. by further proliferation of the cells lining the flask, buds of cells are formed, which become surrounded and isolated by the invading mesoderm. the epithelium forms fine lobules, and develops into a sponge-like structure. during this stage, hematopoietic bone-marrow precursors migrate into the thymus. normal development is dependent on the interaction between the epithelium and the hematopoietic thymocytes. iodine is also necessary for thymus development and activity. involution the thymus continues to grow after birth reaching the relative maximum size by puberty. it is most active in fetal and neonatal life. it increases to a mass of 20 to 50 grams by puberty. it then begins to decrease in size and activity in a process called thymic involution. after the first year of life the amount of t cells produced begins to fall. fat and connective tissue fills a part of the thymic volume. during involution, the thymus decreases in size and activity. fat cells are present at birth, but increase in size and number markedly after puberty, invading the gland from the walls between the lobules first, then into the cortex and medulla. this process continues into old age, where whether with a microscope or with the human eye, the thymus may be difficult to detect, although typically weighs 5–15 grams. additionally, there is an increasing body of evidence showing that age-related thymic involution is found in most, if not all, vertebrate species with a thymus, suggesting that this is an evolutionary process that has been conserved. the atrophy is due to the increased circulating level of sex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity. severe illness or human immunodeficiency virus infection may also result in involution. function 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 produce 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. clinical significance immunodeficiency as the thymus is where t cells develop, congenital problems with the development of the thymus can lead to immunodeficiency, whether because of a problem with the development of the thymus gland, or a problem specific to thymocyte development. immunodeficiency can be profound. loss of the thymus at an early age through genetic mutation (as in digeorge syndrome, charge syndrome, or a very rare "nude" thymus causing absence of hair and the thymus) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses, protozoa, and fungi. nude mice with the very rare "nude" deficiency as a result of foxn1 mutation are a strain of research mice as a model of t cell deficiency. the most common congenital cause of thymus-related immune deficiency results from the deletion of the 22nd chromosome, called digeorge syndrome. this results in a failure of development of the third and fourth pharyngeal pouches, resulting in failure of development of the thymus, and variable other associated problems, such as congenital heart disease, and abnormalities of mouth (such as cleft palate and cleft lip), failure of development of the parathyroid glands, and the presence of a fistula between the trachea and