Generation of lymphocytes in bone marrow and thymus

The greater part of lymphocyte development in mammals occurs in the specialized environments of the central lymphoid organs—the bone marrow (and the liver in the fetus) for B cells and the thymus for T cells. In the fetus and the juvenile, these tissues are the source of large numbers of new lymphocytes, which migrate to populate the peripheral lymphoid tissues. In mature individuals, development of new T cells in the thymus slows down and T-cell numbers are maintained through division of mature T cells outside of the central lymphoid organs. New B cells, on the other hand, are continually produced from the bone marrow, even in adults.

In this part of the chapter we describe the nature of these primary lymphopoietic environments and the developmental stages through which lymphocytes pass. These stages are defined mainly by the various steps in the assembly and expression of functional antigen receptor genes, and by the appearance of features that distinguish the different functional types of B and T cells. At each step of lymphocyte development, the progress of gene rearrangement is monitored. A successful gene rearrangement that leads to the production of a protein chain serves as a signal for the cell to progress to the next stage of development.

T-cell development is more complicated than B-cell development as it has to accommodate the production of two distinct lineages of T cells with different types of T-cell receptor—α:β and γ:δ (see Section 4-13). The α:β and γ:δ T cells diverge early in T-cell development. There is a further division of the α:β T cells into CD4 and CD8 T cells (see Section 3-12) that occurs in immature T cells after the T-cell receptor genes have been assembled and expressed.

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7-1. Lymphocyte development occurs in specialized environments and is regulated by the somatic rearrangement of the antigen-receptor genes

Certain basic principles apply to the process by which precursor cells develop into committed B or T cells expressing antigen-specific receptors—the immunoglobulins and T-cell receptors, respectively. In both humans and mice this process of lymphocyte differentiation occurs in ordered stages, and these are marked by successive steps in the rearrangement of the antigen-receptor genes and expression of their protein products, as well as by changes in the expression of other cell-surface and intracellular proteins. The successful execution of this intrinsic developmental program requires signals from the specialized microenvironments in which lymphocytes develop—bone marrow and fetal liver for B cells and thymus for T cells. These tissues provide a network of specialized nonlymphoid stromal cells that interact intimately with the developing lymphocytes, providing signals through secreted growth factors and cell-surface molecules that bind receptors on the lymphocyte precursor cells.

The antigen specificity of each individual lymphocyte is determined through the assembly of V, D, and J gene segments to generate rearranged V genes encoding the antigen-receptor variable (V) region (see Sections 4-2 and 4-11). The expression of a complete antigen receptor requires the successful rearrangement of two different genetic loci in order to produce the protein chains of the antigen receptor—the heavy and light chains of immunoglobulins or the α and β chains (or γ and δ chains) of the T-cell receptor. Not all gene rearrangement events are successful, however. Because of the imprecision in the recombination process, not all rearrangements produce a complete in-frame DNA sequence that can be translated into protein. The successful assembly of a V region is monitored for each locus, and defines the different stages of lymphocyte development. A successful gene rearrangement, termed a productive rearrangement, leads to the synthesis of the protein product; this is the signal for the cell to progress to the next stage of development.

In the case of B cells, for example, the assembly of an in-frame heavy-chain VDJ sequence leads to expression of the heavy chain; this is sensed by the cell as a signal to stop heavy-chain locus rearrangement, to divide several times, and then to commence rearrangement of a light-chain locus. Unsuccessful rearrangements that do not result in a protein are termed nonproductive rearrangements, and if no further rearrangement can occur to rescue the situation, the lymphocyte dies.

To survive these first stages of development, therefore, B cells must make a productive rearrangement at the immunoglobulin heavy-chain locus and at one of the two light-chain loci, kappa or lambda. T cells must make productive rearrangements at either the α-chain locus and the β-chain locus, which produces an α:β T cell, or at the γ-chain and δ-chain loci, which produces a γ:δ T cell. Those cells that fail to make the necessary productive rearrangements die in situ by apoptosis.

The events that lead to a B cell with an immunoglobulin B-cell receptor and a T cell with an α:β T-cell receptor have a very close correspondence, and we will discuss these here, leaving aside the complicating factor of rearrangements at the γ and δ loci that are also occurring in the earliest T-cell precursors; these will be returned to later in the chapter. Only one gene locus is rearranged at a time, and the loci are each rearranged in a fixed sequence. Both B cells and T cells rearrange the locus that contains D gene segments first; in the case of B cells this is the immunoglobulin heavy-chain locus; for T cells it is the T-cell receptor β-chain locus. Only if a productive rearrangement is made do developing B cells go on to rearrange a light-chain locus, and T cells go on to rearrange the α-chain locus.

The protein product of each antigen-receptor locus is intended to be expressed paired with another chain; an α and a β chain make up the T-cell receptor, for example (see Fig. 3.12). How, therefore, can a developing T cell test whether a productive rearrangement of a β chain-gene has occurred when it has not yet rearranged the α-chain locus? The solution is that both B cells and T cells produce invariant ‘surrogate’ partner chains at this stage in development. These surrogates pair with the heavy chain or the β chain to produce ‘receptors’ that can be expressed at the cell surface. Formation of these receptors generates signals that result in the cessation of VDJ rearrangement. This is followed by several rounds of cell division before the cells proceed to the next stage of development, which is V to J rearrangement at a light-chain locus in B cells and at the α-chain locus in T cells. If this rearrangement is productive, the lymphocyte can then express a bona fide immunoglobulin or T-cell receptor at the surface.

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7-2. B cells develop in the bone marrow with the help of stromal cells and achieve maturity in peripheral lymphoid organs

B-cell development is dependent on the nonlymphoid stromal cells of the bone marrow; stem cells isolated from the bone marrow and grown in culture fail to differentiate into B cells unless bone marrow stromal cells are also present. The stroma, whose name derives from the Greek word for a mattress, thus provides a necessary support for B-cell development. The contribution of the stromal cells is twofold. First, they form specific adhesive contacts with the developing B-lineage cells by interactions between cell-adhesion molecules and their ligands. Second, they provide growth factors that stimulate lymphocyte differentiation and proliferation (Fig. 7.3).

Figure 7.3

The early stages of B-cell development are dependent on bone marrow stromal cells. The upper panels show the interactions between precursor B cells and stromal cells that are required for the development to the immature B-cell stage. The designations (more...)

A number of bone marrow growth factors have been identified and their functions elucidated. The growth of early B-lineage cells is stimulated by stem-cell factor (SCF), a membrane-bound cytokine present on stromal cells, which interacts with the cell-surface receptor tyrosine kinase Kit on B-cell precursors. Developing B cells at later stages require the secreted cytokine interleukin-7 (IL-7). The chemokine stromal cell-derived factor 1 or pre-B cell growth-stimulating factor (SDF-1/PBSF) has an important role in the early stages of B-cell development, as shown by the failure of B-cell development in mice lacking the gene for this molecule. SDF-1 is produced constitutively by bone marrow stromal cells and one of its roles may be to retain developing B-cell precursors in the marrow microenvironment. Other adhesion molecules and growth factors produced by stromal cells are known to have roles in B-cell development; this is an active area of research and a full understanding of the factors that regulate B-cell differentiation has yet to be achieved.

As B-lineage cells mature, they migrate within the marrow, remaining in contact with the stromal cells. The earliest stem cells lie in a region called the subendosteum, which is adjacent to the inner bone surface. As maturation proceeds, B-lineage cells move toward the central axis of the marrow cavity (Fig. 7.4). Later stages of maturation become less dependent on contact with stromal cells, and the final stages of development of immature B cells into mature B cells occur in peripheral lymphoid organs such as the spleen.

Figure 7.4

B-lineage cells move within the bone marrow toward its central axis as they mature. Part of a transverse section of a rat femur photographed through a fluorescence microscope to identify cells (green) stained for the enzyme terminal deoxynucleotidyl transferase (more...)

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7-3. Stages in B-cell development are distinguished by the expression of immunoglobulin chains and particular cell-surface proteins

The stages in primary B-cell development are defined by the sequential rearrangement and expression of heavy- and light-chain immunoglobulin genes (Fig. 7.5). The first classification of B-lineage cells into different developmental stages was made according to whether they expressed no immunoglobulin chains, or the immunoglobulin heavy chain only, or both heavy and light chains. Subsequently, intermediate differentiation stages have been distinguished on the basis of the expression of other cell-surface proteins, together with direct DNA analysis of the state of the immunoglobulin gene loci.

Figure 7.5

The development of a B-lineage cell proceeds through several stages marked by the rearrangement and expression of the immunoglobulin genes. The stem cell has not yet begun to rearrange its immunoglobulin (Ig) gene segments; they are in the germline configuration (more...)

The earliest B-lineage cells are known as pro-B cells, as they are progenitor cells with limited self-renewal capacity. They are derived from pluripotent hematopoietic stem cells and are identified by the appearance of cell-surface proteins characteristic of early B-lineage cells. Rearrangement of the immunoglobulin heavy-chain locus takes place in pro-B cells; DH to JH joining at the early pro-B cell stage is followed by VH to DJH joining at the late pro-B cell stage.

Productive VDJH joining leads to the expression of an intact μ heavy chain, which is the hallmark of the next main stage of development, the pre-B cell stage. The μ chain in large pre-B cells is expressed intracellularly and possibly in small amounts at the cell surface, in combination with a surrogate light chain, to form the pre-B-cell receptor. Expression of the pre-B-cell receptor signals the cell to halt heavy-chain locus rearrangement and production of the surrogate light chain, and to divide several times before giving rise to small pre-B cells, in which light-chain rearrangements begin. Once a light-chain gene is assembled and a complete IgM molecule is expressed on the cell surface, the cell is defined as an immature B cell. The expression of the immunoglobulin heavy and light chains are key milestones in this differentiation pathway. These events do more than simply delineate stages of the pathway; the expression of an intact heavy chain, and later of a complete immunoglobulin molecule, actively regulates progression from one stage to the next.

All development up to this point has taken place in the bone marrow and is independent of antigen. Immature B cells now undergo selection for self-tolerance and subsequently for the ability to survive in the peripheral lymphoid tissues. B cells that survive in the periphery undergo further differentiation to become mature B cells that express IgD in addition to IgM. These cells, also called naive B cells until they encounter their specific antigen, recirculate through peripheral lymphoid tissues, where they may encounter and be activated by the appropriate foreign antigen.

As B cells develop from pro-B cells to mature B cells, they express proteins other than immunoglobulin that are characteristic of each stage. Many of these proteins are expressed on the cell surface and are useful markers for B-lineage cells at different developmental stages. Fig. 7.6 summarizes their expression patterns. The functions of some of these proteins are understood, whereas others serve at present simply as useful signposts for the study of B-cell development. One of the first identifiable proteins expressed on the surface of B-lineage cells is CD45R (known in mice as B220). This is a B-cell-specific form of the CD45 protein originally known as the common leukocyte antigen; T cells, monocytes, and neutrophils express other variants of this protein. CD45R, which is expressed throughout B-cell development from pro-B cells right up to the antibody-secreting plasma cells, is a protein tyrosine phosphatase that functions in B-cell receptor signaling (see Section 6-7). Another protein that is expressed throughout B-cell development is CD19, which also participates in B-cell receptor signaling. Since signaling through the pre-B and B-cell receptors guides B-cell development, the earliest B-cell precursors begin to assemble the signaling components of the receptor complex including CD45R and CD19. The earliest B-cell precursors also express the receptor for IL-7, which is an essential growth factor for both developing B cells and T cells. Blocking signaling by infusion of an anti-IL-7 antibody will halt B-cell development, as will mutations that inactivate either IL-7 or its receptor.

Figure 7.6

The correlation of the stages of B-cell development with immunoglobulin gene segment rearrangement and expression of cell-surface proteins. Stages of B-cell development are defined by which gene segments are undergoing rearrangement as well as by cell-surface (more...)

Another cell-surface protein first detected at the pro-B cell stage is CD43 (the mucin leukosialin), but this is lost as cells progress to become immature B cells. CD43 functions both as an adhesion molecule that may guide cell-cell inter-actions—for example those of B-cell precursors with stromal cells—and also as a signaling molecule, although not as part of the B-cell receptor complex. Exactly why CD43 is expressed at these early stages of B-cell development, but not later, is not yet known. Other cell-surface molecules expressed during early stages of B-cell development include the heat-stable antigen (HSA, CD24) and the aminopeptidase BP-1. The functions of these molecules in B-cell development are unknown, although B cells apparently develop normally in mice lacking BP-1. At the late pro-B cell stage, Kit, the receptor for SCF-1 mutates. Kit is a factor that stimulates both lymphoid and myeloid development in the bone marrow. After Kit turns off, at the large pre-B cell stage, the low affinity IL-2 receptor, CD25, is expressed. Signaling through Kit, in concert with IL-7 and other stromal-derived signals, promotes pro- and pre-B cell proliferation (see Fig. 7.3).

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7-4. T cells also originate in the bone marrow, but all the important events in their development occur in the thymus

T lymphocytes develop from a common lymphoid progenitor in the bone marrow that also gives rise to B lymphocytes, but those progeny destined to give rise to T cells leave the bone marrow and migrate to the thymus (see Fig. 7.2). This is the reason they are called thymus-dependent (T) lymphocytes or T cells. The thymus is situated in the upper anterior thorax, just above the heart. It consists of numerous lobules, each clearly differentiated into an outer cortical region—the thymic cortex—and an inner medulla (Fig. 7.7). In young individuals, the thymus contains large numbers of developing T-cell precursors embedded in a network of epithelia known as the thymic stroma, which provides a unique microenvironment for T-cell development analogous to that provided by the stromal cells of the bone marrow.

Figure 7.7

The cellular organization of the human thymus. The thymus, which lies in the midline of the body, above the heart, is made up of several lobules, each of which contains discrete cortical (outer) and medullary (central) regions. As shown in the diagram (more...)

The thymic stroma arises early in embryonic development from the endo dermal and ectodermal layers of embryonic structures known as the third pharyngeal pouch and third branchial cleft. Together these epithelial tissues form a rudimentary thymus, or thymic anlage. The thymic anlage then attracts cells of hematopoietic origin, which colonize it; these give rise to large numbers of thymocytes, which are committed to the T-cell lineage, and the intrathymic dendritic cells. The thymocytes are not simply passengers within the thymus; they influence the arrangement of the thymic epithelial cells on which they depend for survival, inducing the formation of a reticular epithelial structure that surrounds the developing thymocytes (Fig. 7.8). The thymus is independently colonized by numerous macrophages, also of bone marrow origin.

Figure 7.8

The epithelial cells of the thymus form a network surrounding developing thymocytes. In this scanning electron micrograph of the thymus, the developing thymocytes (the spherical cells) occupy the interstices of an extensive network of epithelial cells. (more...)

The cellular architecture of the human thymus is illustrated in Fig. 7.7. Bone marrow derived cells are differentially distributed between the thymic cortex and medulla; the cortex contains only immature thymocytes and scattered macrophages, whereas more mature thymocytes, along with dendritic cells and macrophages, are found in the medulla. This reflects the different developmental events that occur within these two compartments, as we will discuss further in Section 7-7.

The importance of the thymus in immunity was first discovered through experiments on mice, and indeed, most of our knowledge of T-cell development within the thymus comes from the mouse. It was found that surgical removal of the thymus (thymectomy) at birth resulted in immunodeficient mice, focusing interest on this organ at a time when the difference between T and B lymphocytes in mammals had not yet been defined. Much evidence has accumulated since to establish the importance of the thymus in T-cell development, including observations of immunodeficient children. Thus, for example, in DiGeorge's syndrome in humans, and in mice with the nude mutation (which also causes hairlessness), the thymus fails to form and the affected individual produces B lymphocytes but few T lymphocytes.

The crucial role of the thymic stroma in inducing the differentiation of bone marrow-derived precursor cells can be demonstrated by tissue grafts between two mutant mice, each lacking mature T cells for a different reason. In nude mice the thymic epithelium fails to differentiate, whereas in scid mice B and T lymphocytes fail to develop because of a defect in T-cell receptor gene rearrangement (see Section 4-5). Reciprocal grafts of thymus and bone marrow between these immunodeficient strains show that nude bone marrow precursors develop normally in a scid thymus (Fig. 7.9). Thus, the defect in nude mice is in the thymic stromal cells. Transplanting a scid thymus into nude mice leads to T-cell development. However, scid bone marrow cannot develop T cells even in a wild-type recipient.

Figure 7.9

The thymus is critical for the maturation of bone marrow-derived cells into T cells. Mice with the scid mutation (upper left photograph) have a defect that prevents lymphocyte maturation, whereas mice with the nude mutation (upper right photograph) have (more...)

In mice, the thymus continues to develop for 3 to 4 weeks after birth, whereas in humans it is fully developed at birth. The rate of T-cell production by the thymus is greatest before puberty. After puberty, the thymus begins to shrink and the production of new T cells in adults is lower, although it does continue throughout life. In both mice and humans, removal of the thymus after puberty is not accompanied by any notable loss of T-cell function. Thus, it seems that once the T-cell repertoire is established, immunity can be sustained without the production of significant numbers of new T cells; the pool of peripheral T cells is instead maintained by the division of mature T cells.

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7-5. Most developing T cells die in the thymus

T-cell precursors arriving in the thymus from the bone marrow spend up to a week differentiating there before they enter a phase of intense proliferation. In a young adult mouse the thymus contains around 108 to 2 × 108 thymocytes. About 5 × 107 new cells are generated each day; however, only about 106 to 2 × 106 (roughly 2–4%) of these will leave the thymus each day as mature T cells. Despite the disparity between the numbers of T cells generated daily in the thymus and the number leaving, the thymus does not continue to grow in size or cell number. This is because approximately 98% of the thymocytes that develop in the thymus also die within the thymus. No widespread damage is seen, indicating that death is occurring by apoptosis rather than by necrosis (see Section 1-11).

Changes in the plasma membrane of cells undergoing apoptosis lead to their rapid phagocytosis, and apoptotic bodies, which are the residual condensed chromatin of apoptotic cells, are seen inside macrophages throughout the thymic cortex (Fig. 7.10). This apparently profligate waste of thymocytes is a crucial part of T-cell development as it reflects the intensive screening that each new thymocyte undergoes for the ability to recognize self MHC and for self tolerance.

Figure 7.10

Developing T cells that undergo apoptosis are ingested by macrophages in the thymic cortex. Panel a shows a section through the thymic cortex and part of the medulla in which cells have been stained for apoptosis with a red dye. Thymic cortex is to the (more...)

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7-6. Successive stages in the development of thymocytes are marked by changes in cell-surface molecules

Developing thymocytes pass through a series of distinct phases that are marked by changes in the status of T-cell receptor genes and in the expression of the T-cell receptor, and by changes in expression of cell-surface proteins such as the CD3 complex and the co-receptor proteins CD4 and CD8. These surface changes reflect the state of functional maturation of the cell. Particular combinations of cell-surface proteins can thus be used as markers for T cells at different stages of differentiation. The principal stages are summarized in Fig. 7.11. Two distinct lineages of T cells—α:β and γ:δ, which have different types of T-cell receptor—are produced early in T-cell development. Later, α:β T cells develop into two distinct functional subsets, CD4 and CD8 T cells.

Figure 7.11

Changes in cell-surface molecules allow thymocyte populations at different stages of maturation to be distinguished. The most important cell-surface molecules for identifying thymocyte subpopulations have been CD4, CD8, and T-cell receptor complex molecules (more...)

When progenitor cells first enter the thymus from the bone marrow, they lack most of the surface molecules characteristic of mature T cells and their receptor genes are unrearranged. These cells give rise to the major population of α:β T cells and the minor population of γ:δ T cells. If injected into the peripheral circulation, these lymphoid progenitors can even give rise to B cells and NK cells (see Section 1-1). Interactions with the thymic stroma trigger an initial phase of differentiation along the T-cell lineage pathway followed by cell proliferation, and the expression of the first cell-surface molecules specific for T cells, for example CD2 and (in mice) Thy-1. At the end of this phase, which can last about a week, the thymocytes bear distinctive markers of the T-cell lineage, but they do not express any of the three cell-surface markers that define mature T cells. These are the CD3:T-cell receptor complex and the co-receptors CD4 or CD8. Because of the absence of CD4 and CD8 such cells are called ‘double-negative’ thymocytes (see Fig. 7.11).

In the fully developed thymus, these immature double-negative T cells form approximately 60% of a small, highly heterogeneous pool of CD4- CD8- cells (about 5% of total thymocytes), which also includes two populations of more mature T cells that belong to minority lineages. One of these, representing about 20% of all the double-negative cells in the thymus, or 1% of total thymocytes, comprises cells that have rearranged and are expressing the genes encoding the γ:δ T-cell receptor; we will return to these cells in Section 7-13. The second, representing another 20% of all double negatives, includes cells bearing α:β T-cell receptors of a very limited diversity; these cells also express the NK1.1 receptor commonly found on NK cells, hence they are known as ‘NK1.1+ T cells’ (sometimes simply called NK T cells). NK T cells are activated as part of the early response to many infections; they differ from the major lineage of α:β T cells in recognizing CD1 molecules rather than MHC class I or MHC class II molecules (see Section 5-18) and they are not shown in Fig. 7.11. In this and subsequent discussions, we will reserve the term double-negative thymocytes for the immature thymocytes that do not yet express a complete T-cell receptor molecule. These cells give rise to both γ:δ and α:β T cells (see Fig. 7.11). Most of them develop along the α:β pathway.

The α:β pathway is shown in more detail in Fig. 7.12. The double-negative stage can be subdivided on the basis of expression of the adhesion molecule CD44, CD25 (the α chain of the IL-2 receptor), and c-Kit, the receptor for the hematopoietic cytokine, stem cell factor. At first, double-negative thymocytes express c-Kit and CD44 but not CD25; in these cells, the genes encoding both chains of the T-cell receptor are in the germline configuration. As the thymocytes mature further, they begin to express CD25 on their surface and, later still, expression of CD44 and c-Kit is reduced. In these latter cells, which are known as CD44low CD25+ cells, rearrangement of the T-cell receptor β-chain locus occurs. Cells that fail to make a successful rearrangement of the β locus remain in the CD44low CD25+ stage and soon die, whereas cells that make productive β-chain gene rearrangements and express the β chain lose expression of CD25 once again. The functional significance of the transient expression of CD25 is unclear; T cells develop normally in mice in which the IL-2 gene has been deleted by gene knockout (see Appendix I, Section A-47); however, another cytokine, IL-15, also binds to the IL-2 receptor and may be able to compensate for the loss of IL-2. By contrast, c-Kit is quite important for the development of the earliest double-negative thymocytes in that mice lacking c-Kit have a markedly reduced number of double-negative T cells. In addition, the IL-7 receptor is also essential for early T-cell development, as T cells do not develop in either humans or mice when this receptor is defective.

Figure 7.12

The correlation of stages of α:β T-cell development with T-cell receptor gene rearrangement and expression of cell-surface proteins. Lymphoid precursors are triggered to proliferate and become thymocytes committed to the T-cell lineage (more...)

The β chains expressed by CD44low CD25+ thymocytes pair with a surrogate α chain called pTα (pre-T-cell α), which allows them to assemble a pre-T-cell receptor that is analogous in structure and function to the pre-B-cell receptor. The pre-T-cell receptor is expressed on the cell surface as a complex with the CD3 molecules that provide the signaling components of T-cell receptors (see Section 6-6). The assembly of the CD3:pre-T-cell receptor complex leads to cell proliferation, the arrest of further β-chain gene rearrangements, and the expression of CD8 and CD4. These double-positive thymocytes comprise the vast majority of thymocytes. Once the large double-positive thymocytes cease to proliferate and become small double-positive cells, the α-chain locus begins to rearrange. As we will see later in this chapter, the structure of the α locus allows multiple successive rearrangement attempts, so that a successful rearrangement at the α-chain locus is achieved in most developing thymocytes. Thus most double-positive cells produce an α:β T-cell receptor.

Small double-positive thymocytes initially express low levels of the T-cell receptor. Most of these cells bear receptors that cannot recognize self MHC molecules; they are destined to fail positive selection and die. On the other hand, those double-positive cells that recognize self MHC and can therefore undergo positive selection, go on to mature and express high levels of the T-cell receptor. Concurrently, they cease to express one or other of the two co-receptor molecules, becoming either CD4 or CD8 single-positive thymocytes. Thymocytes also undergo negative selection during and after the double-positive stage in development, which eliminates those cells capable of responding to self antigens. Approximately 2% of the double positives survive this dual screening and mature as single-positive T cells that are gradually exported from the thymus to form the peripheral T-cell repertoire. The time between the entry of a T-cell progenitor into the thymus and the export of its mature progeny is estimated to be around 3 weeks in the mouse.

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7-7. Thymocytes at different developmental stages are found in distinct parts of the thymus

The thymus is divided into two main regions, a peripheral cortex and a central medulla (see Fig. 7.7). Most T-cell development takes place in the cortex; only mature single-positive thymocytes are seen in the medulla. At the outer edge of the cortex, in the subcapsular region of the thymus (Fig. 7.13), large immature double-negative thymocytes proliferate vigorously; these cells are thought to represent the thymic progenitors and their immediate progeny and will give rise to all subsequent thymocyte populations. Deeper in the cortex, most of the thymocytes are small double-positive cells. The cortical stroma is composed of epithelial cells with long branching processes that express both MHC class II and MHC class I molecules on their surface. The thymic cortex is densely packed with thymocytes, and the branching processes of the thymic cortical epithelial cells make contact with almost all cortical thymocytes (see Fig. 7.8). Contact between the MHC molecules on thymic cortical epithelial cells and the receptors of developing T cells has a crucial role in positive selection, as we will see later in this chapter.

Figure 7.13

Thymocytes at different developmental stages are found in distinct parts of the thymus. The earliest cells to enter the thymus are found in the subcapsular region of the cortex. As these cells proliferate and mature into double-positive thymocytes, they (more...)

The function of the medulla of the thymus is less well understood. It contains relatively few thymocytes, and those that are present are single-positive cells resembling mature T cells. These cells probably include newly mature T cells that are leaving the thymus through the medulla. In addition, they may also include other populations of mature T cells that remain within the medulla or return to it from the periphery to perform some specialized function, such as the elimination of infectious agents within the thymus. Before they mature, the developing thymocytes must undergo negative selection to remove self-reactive cells. We will see that this selective process is carried out mainly by the dendritic cells, which are particularly numerous at the cortico-medullary junction, and by the macrophages that are scattered in the cortex but are also abundant in the thymic medulla.

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Summary

B cells are generated and develop in the specialized microenvironment of the bone marrow, while the thymus provides a specialized and architecturally organized microenvironment for the development of T cells. As B cells differentiate from primitive stem cells, they proceed through stages that are marked by the sequential rearrangement of immunoglobulin gene segments to generate a diverse repertoire of antigen receptors. This developmental program also involves changes in the expression of other cellular proteins. Precursors of T cells migrate from the bone marrow and mature in the thymus. This process is similar to that for B cells, including the sequential rearrangement of antigen receptor gene segments. Developing T cells pass through a series of stages that can be distinguished by the differential expression of CD44 and CD25, the CD3:T-cell receptor complex proteins, and the co-receptor proteins CD4 and CD8. The development of both T and B cells is guided by the environment, particularly by stromal cells that provide contact-dependent signals and growth factors for developing lymphocytes. In the case of T cells, development is compartmentalized, with different types of stromal cells in the thymic cortex and medulla. Most steps in T-cell differentiation occur in the cortex of the thymus. The thymic medulla contains mainly mature T cells. Lymphocyte development is accompanied by extensive cell death, reflecting intense selection and the elimination of those cells with inappropriate receptor specificities. B cells are produced throughout life, whereas T-cell production from the thymus slows down after puberty.