Response to antigen

Unrecombined (germline) DNA

Bone marrow

None

Pro-T

Unrecombined (germline) DNA

None

Pre-T

Double positive

Recombined ß chain gene

None

Recombined ß, a chain genes [V(D)J-C]; ß and a chain mRNA

Membrane aß TCR

CD4+CD8+ TCR/CD3lQ

Thymus

Positive and negative selection

Single positive (immature T cell)

Recombined ß, a chain genes [V(D)J-C]; ß and a chain mRNA

Membrane aß TCR

CD4+CD8- or CD4-CD8+ TCR/CD3hi

Naive mature T cell

Recombined ß, a chain genes [V(D)J-C]; ß and a chain mRNA

Membrane aß TCR

CD4+CD8- or CD4-CD8+ TCR/CD3hi

Periphery

Activation (proliferation and differentiation)

FIGURE 8-19 Stages of T cell maturation. Events corresponding to each stage of T cell maturation from a bone marrow stem cell to a mature T lymphocyte are illustrated. Several surface markers in addition to those shown have been used to define distinct stages of T cell maturation.

(perhaps longer than 20 years in humans) and accumulate with age, the need to generate new T cells decreases as individuals age.

T lymphocytes originate from precursors that arise in the fetal liver and adult bone marrow and seed the thymus. These precursors are multipotent progenitors that enter the thymus from the blood stream, crossing the endothelium of a postcapillary venule in the cortico-medullary junction region of the thymus. In mice, immature lymphocytes are first detected in the thymus on the eleventh day of the normal 21-day gestation. This corresponds to about week 7 or 8 of gestation in humans. Developing T cells in the thymus are called thymocytes. The most immature thymocytes are found in the subcap-sular sinus and outer cortical region of the thymus. From here, the thymocytes migrate into and through the cortex, where most of the subsequent maturation events occur. It is in the cortex that the thymocytes first express Y8 and ap TCRs. The ap T cells mature into CD4+ class II MHC-restricted or CD8+ class I MHC-restricted T cells as they leave the cortex and enter the medulla. From the medulla, CD4+ and CD8+ single-positive thymocytes exit the thymus through the circulation. In the following sections, we discuss the maturation of ap T cells; y8 T cells are discussed later in the chapter.

The thymic environment provides stimuli that are required for the proliferation and maturation of thymo-cytes. Many of these stimuli come from thymic cells other than the maturing T cells. Within the cortex, thymic cortical epithelial cells form a meshwork of long cytoplas-mic processes, around which thymocytes must pass to reach the medulla. Epithelial cells of a distinct type known as thymic medullary epithelial cells are also present in the medulla. Bone marrow-derived dendritic cells are present at the corticomedullary junction and within the medulla, and macrophages are present primarily within the medulla. The migration of thymocytes through this anatomic arrangement allows physical interactions between the thymocytes and these other cells that are necessary for the maturation and selection of the T lymphocytes.

Two types of molecules produced by the nonlymphoid thymic cells are important for T cell maturation. The first are class I and class II MHC molecules, which are expressed on epithelial cells and dendritic cells in the thymus. The interactions of maturing thymocytes with these MHC molecules within the thymus are essential for the selection of the mature T cell repertoire, as we will discuss later. Second, thymic stromal cells, including epithelial cells, secrete cytokines and chemokines, which respectively stimulate the proliferation of immature T cells and orchestrate the cortical to medullary transit of developing ap lineage thymocytes. The best defined of these cytokines is IL-7, which was mentioned earlier as a critical lymphopoietic growth factor. The movement of cells into and through the thymus is driven by chemokines. The progenitors of thymocytes express the chemokine receptor CCR9, which binds to the chemokine CCL25, which is produced in the thymic cortex. Entry of precursors into the thymus is dependent on CCL25 and CCR9. Chemokines such as CCL21 and CCL19, which are recognized by the CCR7 chemokine receptor on thymocytes, mediate the guided movement of developing T cells from the cortex to the medulla.

The rates of cell proliferation and apoptotic death are extremely high in cortical thymocytes. A single precursor gives rise to many progeny, and 95% of these cells die by apoptosis before reaching the medulla. The cell death is due to a combination of factors including a failure to productively rearrange the TCR p chain gene and thus to negotiate the pre-TCR/p selection checkpoint described later, a failure to be positively selected by MHC molecules in the thymus, and self antigen-induced negative selection (see Figs. 8-3 and 8-4). Cortical thymocytes are also sensitive to irradiation and glucocorticoids. In vivo, high doses of glucocorticoids induce apoptotic death of immature cortical thymocytes.

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