TCell Maturation and the Thymus

Progenitor T cells from the early sites of hematopoiesis begin to migrate to the thymus at about day 11 of gestation in mice and in the eighth or ninth week of gestation in humans. In a manner similar to B-cell maturation in the bone marrow, T-cell maturation involves rearrangements of the germ-line TCR genes and the expression of various membrane markers. In the thymus, developing T cells, known as thymocytes, proliferate and differentiate along developmental pathways that generate functionally distinct subpopulations of mature T cells.



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Engagement of TcR by Peptide: MHC Initiates Signal Transduction

■ T-Cell Maturation and the Thymus

■ Thymic Selection of the T-Cell Repertoire

■ TH-Cell Activation

■ T-Cell Differentiation

■ Cell Death and T-Cell Populations

■ Peripheral 78 T-Cells

As indicated in Chapter 2, the thymus occupies a central role in T-cell biology. Aside from being the main source of all T cells, it is where T cells diversify and then are shaped into an effective primary T-cell repertoire by an extraordinary pair of selection processes. One of these, positive selection, permits the survival of only those T cells whose TCRs are capable of recognizing self-MHC molecules. It is thus responsible for the creation of a self-MHC-restricted repertoire of T cells. The other, negative selection, eliminates T cells that react too strongly with self-MHC or with self-MHC plus self-peptides. It is an extremely important factor in generating a primary T-cell repertoire that is self-tolerant.

As shown in Figure 10-1, when T-cell precursors arrive at the thymus, they do not express such signature surface markers of T cells as the T-cell receptor, the CD3 complex, or the coreceptors CD4 and CD8. In fact, these progenitor cells have




Development of ap T cells in the mouse. T-cell precursors arrive at the thymus from bone marrow via the bloodstream, undergo development to mature T cells, and are exported to the periphery where they can undergo antigen-induced activation and differentiation into effector cells and memory cells. Each stage of development is characterized by stage-specific intracellular events and the display of distinctive cell-surface markers.





Peripheral tissues

TCR locus rearrangement

RAG expression —

Surface markers

Hematopoietic stem cell (HSC)

c-Kit CD25 CD44

Common lymphoid precursor migration

T-cell precursor

Pro-T cell (double negative, DN)

Pre-T cell (double CD3 negative, DN)

Pro-T cell (double positive, DP)



Tc cell migration



chain Pre-Ta

TCR a chain

CD4 and CD8

CD4 or CD8

on not yet rearranged their TCR genes and do not express proteins, such as RAG-1 and RAG-2, that are required for rearrangement. After arriving at the thymus, these T-cell precursors enter the outer cortex and slowly proliferate.Dur-ing approximately three weeks of development in the thymus, the differentiating T cells progress through a series of stages that are marked by characteristic changes in their cell-surface phenotype. For example, as mentioned previously, thymocytes early in development lack detectable CD4 and CD8. Because these cells are CD4~CD8~, they are referred to as double-negative (DN) cells.

Even though these coreceptors are not expressed during the DN early stages, the differentiation program is progressing and is marked by changes in the expression of such cell surface molecules as c-Kit, CD44, and CD25. The initial thymocyte population displays c-Kit, the receptor for stem-cell growth factor, and CD44, an adhesion molecule involved in homing; CD25, the p-chain of the IL-2 receptor, also appears on early-stage DN cells. During this period, the cells are proliferating but the TCR genes remain unrearranged. Then the cells stop expressing c-Kit, markedly reduce CD44 expression, turn on expression of the recombinase genes RAG-1 and RAG-2 and begin to rearrange their TCR genes. Although it is not shown in Figure 10-1, a small percentage (<5%) of thymocytes productively rearrange the 7- and 8-chain genes and develop into double-negative CD3+ 78 T cells. In mice, this thymocyte subpopulation can be detected by day 14 of gestation, reaches maximal numbers between days 17 and 18, and then declines until birth (Figure 10-2).

Most double-negative thymocytes progress down the ap developmental pathway. They stop proliferating and begin to rearrange the TCR p-chain genes, then express the p chain. Those cells of the ap lineage that fail to productively rearrange and express p chains die. Newly synthesized p chains combine with a 33-kDa glycoprotein known as the pre-Ta chain and associate with the CD3 group to form a novel com-

15 16 17 18 19 Birth Days of gestation


15 16 17 18 19 Birth Days of gestation



Time course of appearance of 78 thymocytes and ap thymocytes during mouse fetal development. The graph shows the percentage of CD3+ cells in the thymus that are double-negative (CD4~8~) and bear the 78 T-cell receptor (black) or are doublepositive (CD4+8+) and bear the ap T-cell receptor (blue).

plex called the pre-T-cell receptor or pre-TCR (Figure 10-3). Some researchers have suggested that the pre-TCR recognizes some intra-thymic ligand and transmits a signal through the CD3 complex that activates signal-transduction pathways that have several effects:

■ Indicates that a cell has made a productive TCR (3-chain rearrangement and signals its further proliferation and maturation.



Cell becomes permissive for TCR a-chain locus arrangement

Stimulates expression of CD4 and CD8 coreceptors




Stops additional TCR ß-chain locus arrangements (allelic exclusion)

Stimulates expression of CD4 and CD8 coreceptors

Stimulates proliferation

Stops additional TCR ß-chain locus arrangements (allelic exclusion)

Stimulates proliferation

Structure and activity of the pre-T-cell receptor (pre-TCR). Binding of ligands yet to be identified to the pre-TCR generates intracellular signals that induce a variety of processes.

■ Suppresses further rearrangement of TCR p-chain genes, resulting in allelic exclusion.

■ Renders the cell permissive for rearrangement of the TCR a chain.

■ Induces developmental progression to the CD4+8 + double-positive state.

After advancing to the double-positive (DP) stage, where both CD4 and CD8 coreceptors are expressed, the thymocytes begin to proliferate. However, during this proliferative phase, TCR a-chain gene rearrangement does not occur; both the RAG-1 and RAG-2 genes are transcriptionally active, but the RAG-2 protein is rapidly degraded in proliferating cells, so rearrangement of the a-chain genes cannot take place. The rearrangement of a-chain genes does not begin until the double-positive thymocytes stop proliferating and RAG-2 protein levels increase. The proliferative phase prior to the rearrangement of the a-chain increases the diversity of the T-cell repertoire by generating a clone of cells with a single TCR p-chain rearrangement. Each of the cells within this clone can then rearrange a different a-chain gene, thereby generating a much more diverse population than if the original cell had first undergone rearrangement at both the p-and a-chain loci before it proliferated. In mice, the TCR a-chain genes are not expressed until day 16 or 17 of gestation; double-positive cells expressing both CD3 and the ap T-cell receptor begin to appear at day 17 and reach maximal levels about the time of birth (see Figure 10-2). The possession of a complete TCR enables DP thymocytes to undergo the rigors of positive and negative selection.

T-cell development is an expensive process for the host. An estimated 98% of all thymocytes do not mature—they die by apoptosis within the thymus either because they fail to make a productive TCR-gene rearrangement or because they fail to survive thymic selection. Double-positive thymocytes that express the ap TCR-CD3 complex and survive thymic selection develop into immature single-positive CD4+ thymocytes or single-positive CD8+ thymocytes. These single-positive cells undergo additional negative selection and migrate from the cortex to the medula, where they pass from the thymus into the circulatory system.

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