Structure

The thymus consists of lobules of loosely packed epithelial cells, each covered by a connective tissue capsule. The outer part of each lobule, the cortex, is densely infiltrated with lymphocytes (or thymocytes), but the inner medulla contains fewer lymphocytes, and the epithelial cells are clearly visible (Figure 12-3). Within the medulla are also found round, layered bodies called thymic or Hassall’s corpuscles. These contain keratin, and the remains of a small blood vessel may be found at their center. In cattle these corpuscles may contain immunoglobulin A (Chapter 16). An abnormally thick basement membrane and a continuous layer of epithelial cells surround the capillaries that supply the thymic cortex. This barrier prevents circulating foreign antigens from entering the cortex. No lymphatic vessels leave the thymus. As an animal ages, the thymus shrinks and is gradually replaced by fat. However, the aged thymus still contains small amounts of lymphoid tissue and remains functionally active.

Function

The functions of the thymus are best demonstrated by studying the effects of its removal in rodents. These effects depend on the age of the animal. For example, mice thymectomized within a day of birth become susceptible to infections and may fail to grow. These animals have very few circulating lymphocytes and cannot reject foreign organ grafts because they lose the ability to mount cell-mediated immune responses (Table 12-2). In contrast, adult thymectomy has no immediate obvious effect. But if these mice are monitored for several months, the number of blood lymphocytes and their ability to mount cell-mediated immune responses gradually decline. This suggests that the thymus remains functional in adults, but there is a reservoir of long-lived thymus-derived cells that must be exhausted before the effects of adult thymectomy become apparent (Figure 12-4).

The results of thymectomy indicate that the neonatal thymus is the source of most blood lymphocytes and that these lymphocytes are mainly responsible for mounting cell-mediated immune responses. They are called thymus-derived lymphocytes or T cells. T-cell precursors originate in the bone marrow but then enter the thymus. Once within the thymus, the cells (called thymocytes) divide rapidly. Of the new cells produced, most die by apoptosis, whereas the survivors (about 5% of the total in rodents and about 25% in calves) remain in the thymus for 4 to 5 days before leaving and colonizing the secondary lymphoid organs.

T cells that enter the thymus have two conflicting tasks. They must recognize foreign antigens but at the same time must not respond strongly to normal body constituents (self-antigens). A two-stage selection process in the thymic medulla accomplishes this feat. Thus thymocytes with receptors that bind self-antigens strongly and that could therefore cause autoimmunity are killed by apoptosis. Thymocytes with receptors that cannot bind any major histocompatibility complex (MHC) class II molecules and thus cannot react to any processed antigen are also killed.

On the other hand, those thymocytes that survive this “negative selection” process but can still recognize specific MHC class II–antigen complexes with moderate affinity are stimulated to grow—a process called positive selection. These surviving cells eventually leave the thymus as mature T cells, circulate in the bloodstream, and colonize the secondary lymphoid organs.

Thymic epithelial cells are unusual since they express more than 400 antigens normally expressed in other tissues. In addition, these cells have a very high level of autophagy. As a result, their intracellular antigens are bound to MHC class II molecules and expressed in large amounts on the epithelial cell surfaces. This “promiscuous” antigen presentation ensures that developing T cells are exposed to an unusually diverse array of normal tissue antigens. Since T cells that respond to these antigens will die, the system ensures that those T cells leaving the thymus cannot respond to normal body components.

Thymic Hormones

Within the thymus, cell functions are regulated by a complex mixture of cytokines and small peptides collectively known as thymic hormones. These include peptides variously called thymosins, thymopoietins, thymic humoral factor, thymulin, and the thymostimulins. Thymulin is especially interesting because it is a zinc-containing peptide secreted by the thymic epithelial cells, and it can partially restore T cell function in thymectomized animals. Zinc is an essential mineral for the development of T cells. Consequently, zinc-deficient animals have defective cell-mediated immune responses (Chapter 38). Hassall’s corpuscles play a functional role in regulating thymic activity since they express a growth factor called thymic stromal lymphopoietin. This molecule activates thymic dendritic cells that can stimulate regulatory T cells and controls the positive selection process.

Structure

Like the thymus, the bursa consists of lymphocytes embedded in epithelial tissue. This epithelial tissue lines a hollow sac connected to the cloaca by a duct. Inside the sac, folds of epithelium extend into the lumen, and scattered through the folds are round masses of lymphocytes called lymphoid follicles (Figure 12-6). Each follicle is divided into a cortex and a medulla. The cortex contains lymphocytes, plasma cells, and macrophages. At the corticomedullary junction there is a basement membrane and capillary network on the inside of which are epithelial cells. These medullary epithelial cells are replaced by lymphoblasts and lymphocytes in the center of the follicle. Specialized neuroendocrine dendritic cells of unknown function surround each follicle.

Function

The bursa may be removed either surgically or by infecting newborn chicks with a virus that destroys the bursa (infectious bursal disease virus). Since the bursa shrinks when chicks become sexually mature, bursal atrophy can also be provoked by administration of testosterone. Bursectomized birds have very low levels of antibodies in their blood, and antibody-producing cells disappear from lymphoid organs. However, they still possess circulating lymphocytes and can reject foreign skin grafts. Thus, bursectomy has little effect on the cell-mediated immune response. Bursectomized birds are more susceptible than normal to leptospirosis and salmonellosis but not to intracellular bacteria such as Mycobacterium avium.

Thus the bursa is a primary lymphoid organ that functions as a maturation and differentiation site for the cells of the antibody-forming system. Lymphocytes originating in the bursa are therefore called B cells. The bursa acts like the thymus insofar as immature cells produced in the bone marrow migrate to the bursa. These cells then proliferate rapidly, but 90% to 95% of these eventually die by apoptosis—the negative selection of self-reactive B cells. Once their maturation is completed, the surviving B cells emigrate to secondary lymphoid organs.

Close examination shows that the bursa is not a pure primary lymphoid organ because it can also trap antigens and undertake some antibody synthesis. It also contains a small focus of T cells just above the bursal duct opening. Several different hormones have been extracted from the bursa. The most important of these is a tripeptide (Lys- His-glycylamide) called bursin that activates B cells but not T cells.