T Cell Production and Maturation

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a) A drawing of a femur; a long bone with a round head. B) A cross section of the head of the femur.
(a) Red bone marrow can be found in the head of the femur (thighbone) and is also present in the flat bones of the body, such as the ilium and the scapula. (b) Red bone marrow is the site of production and differentiation of many formed elements of blood, including erythrocytes, leukocytes, and platelets. The yellow bone marrow is populated primarily with adipose cells.

Source: OpenStax Microbiology

OpenStax Microbiology

T cells, like all other white blood cells involved in innate and adaptive immunity, are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow. However, unlike the white blood cells of innate immunity, eventual T cells differentiate first into lymphoid stem cells that then become small, immature lymphocytes, sometimes called lymphoblasts. The first steps of differentiation occur in the red marrow of bones (Figure 18.14), after which immature T lymphocytes enter the bloodstream and travel to the thymus for the final steps of maturation. Once in the thymus, the immature T lymphocytes are referred to as thymocytes.

The maturation of thymocytes within the thymus can be divided into three critical steps of positive and negative selection, collectively referred to as thymic selection. The first step of thymic selection occurs in the cortex of the thymus and involves the development of a functional T-cell receptor (TCR) that is required for activation by APCs. Thymocytes with defective TCRs are removed by negative selection through the induction of apoptosis (programmed controlled cell death). The second step of thymic selection also occurs in the cortex and involves the positive selection of thymocytes that will interact appropriately with MHC molecules. Thymocytes that can interact appropriately with MHC molecules receive a positive stimulation that moves them further through the process of maturation, whereas thymocytes that do not interact appropriately are not stimulated and are eliminated by apoptosis. The third and final step of thymic selection occurs in both the cortex and medulla and involves negative selection to remove self-reacting thymocytes, those that react to self-antigens, by apoptosis. This final step is sometimes referred to as central tolerance because it prevents self-reacting T cells from reaching the bloodstream and potentially causing autoimmune disease, which occurs when the immune system attacks healthy “self” cells.

Despite central tolerance, some self-reactive T cells generally escape the thymus and enter the peripheral bloodstream. Therefore, a second line of defense called peripheral tolerance is needed to protect against autoimmune disease. Peripheral tolerance involves mechanisms of anergy and inhibition of self-reactive T cells by regulatory T cells. Anergy refers to a state of nonresponsiveness to antigen stimulation. In the case of self-reactive T cells that escape the thymus, lack of an essential co-stimulatory signal required for activation causes anergy and prevents autoimmune activation. Regulatory T cells participate in peripheral tolerance by inhibiting the activation and function of self-reactive T cells and by secreting anti-inflammatory cytokines.

It is not completely understood what events specifically direct maturation of thymocytes into regulatory T cells. Current theories suggest the critical events may occur during the third step of thymic selection, when most self-reactive T cells are eliminated. Regulatory T cells may receive a unique signal that is below the threshold required to target them for negative selection and apoptosis. Consequently, these cells continue to mature and then exit the thymus, armed to inhibit the activation of self-reactive T cells.

It has been estimated that the three steps of thymic selection eliminate 98% of thymocytes. The remaining 2% that exit the thymus migrate through the bloodstream and lymphatic system to sites of secondary lymphoid organs/tissues, such as the lymph nodes, spleen, and tonsils, where they await activation through the presentation of specific antigens by APCs. Until they are activated, they are known as mature naïve T cells.

A drawing of the thymus (a structure sitting on the surface of the heart); the spleen (a kidney shaped structure in the upper left abdomen; the right lymphatic duct entering vein (a tube in the neck); lymph nodes (enlarged regions of lymph ducts); and a tonsil in the cheek. A callout shows a micrograph of the thymus which has a surface layer labeled fibrous capsule, a central tissue labeled medulla, out tissue labeled cortex, and lighter branches in the cortex labeled trabeculae.
The thymus is a bi-lobed, H-shaped glandular organ that is located just above the heart. It is surrounded by a fibrous capsule of connective tissue. The darkly staining cortex and the lighter staining medulla of individual lobules are clearly visible in the light micrograph of the thymus of a newborn (top right, LM × 100). (credit micrograph: modification of micrograph provided by the Regents of University of Michigan Medical School © 2012)

Source:

Parker, N., Schneegurt, M., Thi Tu, A.-H., Forster, B. M., & Lister, P. (n.d.). Microbiology. Houston, Texas: OpenStax. Access for free at: https://openstax.org/details/books/microbiology

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