8536d_ch10_221 8/27/02 1:37 PM Page 222 Mac 109 Mac 109: 1254_Bh Goldsby et al./Immunology 5e 222 PART II Generation of B-Cell and T-Cell Responses VISUALIZING CONCEPTS Surface markers Hematopoictic stem cell c-Kit CD25 (HSC) CD44 precursor Blood migration ◎ T-cell precursor TCR locus Pro-t cell 厂Dp ◎ (double TCR RAG Pre-T cell chain expression- Vp-Dp:)B (double CD3 Pre-1 IGURE 10-1 Development of aB Vp-Dp:) ProT cell TCR a CD4 T cells in the mouse. T-cell precursors (double arrive at the thymus from bone mar- chain row via the bloodstream, undergo de- velopment to mature T cells, and are exported to the periphery where they CD8+ CD4+ can undergo antigen-induced activa- tion and differentiation into effector T. cell ells and memory cells. Each stage blood of development is characterized by agespecific intracellular events and Peripheral CD8+ the display of distinctive cell-surfac tissues markers not yet rearranged their TCR genes and do not express pro- on early-stage DN cells. During this period, the cells are pro- arrangement. After arriving at the thymus, these T-cell cells stop expressing c-Kit, markedly reduce CD44 expres precursors enter the outer cortex and slowly proliferate Dur- sion, turn on expression of the recombinase genes RAG-I ing approximately three weeks of development in the thy- and RAG-2 and begin to rearrange their TCR genes. Al mus, the differentiating T cells progress through a series of though it is not shown in Figure 10-1, a small percentage stages that are marked by characteristic changes in their cell-(<5%)of thymocytes productively rearrange the y-and surface phenotype. For example, as mentioned previously, 8-chain genes and develop into double-negative CD3 y8 thymocytes early in development lack detectable CD4 and T cells In mice, this thymocyte subpopulation can be detected CD8. Because these cells are CD4 CD8, they are referred to by day 14 of gestation, reaches maximal numbers between as double-negative (DN)cell ays 17 and 18, and then declines until birth( Figure 10-2) Even though these coreceptors are not expressed during Most double-negative thymocytes progress down the ap the dN early stages, the differentiation program is progress- developmental pathway. They stop proliferating and begin to ing and is marked by changes in the expression of such cell rearrange the TCr B-chain genes, then express the p chain surface molecules as c-Kit, CD44, and CD25. The initial thy- Those cells of the aB lineage that fail to productively re- oocyte population displays c-Kit, the receptor for stem-cell range and express B chains die. Newly synthesized B chains growth factor, and CD44, an adhesion molecule involved in combine with a 33-kDa glycoprotein known as the pre-Ta homing; CD25, the B-chain of the IL-2 receptor, also appears chain and associate with the CD3 group to form a novel com-not yet rearranged their TCR genes and do not express pro￾teins, such as RAG-1 and RAG-2, that are required for re￾arrangement. 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 thy￾mus, 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 CD4CD8, 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 progress￾ing and is marked by changes in the expression of such cell surface molecules as c-Kit, CD44, and CD25. The initial thy￾mocyte population displays c-Kit, the receptor for stem-cell growth factor, and CD44, an adhesion molecule involved in homing; CD25, the -chain of the IL-2 receptor, also appears 222 PART II Generation of B-Cell and T-Cell Responses on early-stage DN cells. During this period, the cells are pro￾liferating but the TCR genes remain unrearranged. Then the cells stop expressing c-Kit, markedly reduce CD44 expres￾sion, turn on expression of the recombinase genes RAG-1 and RAG-2 and begin to rearrange their TCR genes. Al￾though it is not shown in Figure 10-1, a small percentage (5%) of thymocytes productively rearrange the - and -chain genes and develop into double-negative CD3 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  developmental pathway. They stop proliferating and begin to rearrange the TCR -chain genes, then express the  chain. Those cells of the  lineage that fail to productively re￾arrange and express  chains die. Newly synthesized  chains combine with a 33-kDa glycoprotein known as the pre-T chain and associate with the CD3 group to form a novel com￾VISUALIZING CONCEPTS FIGURE 10-1 Development of  T cells in the mouse. T-cell precursors arrive at the thymus from bone mar￾row via the bloodstream, undergo de￾velopment to mature T cells, and are exported to the periphery where they can undergo antigen-induced activa￾tion 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. Hematopoietic stem cell (HSC) Common lymphoid precursor T-cell precursor c-Kit CD3 CD44 Pre-Tα TCR β chain TCR α chain CD4 and CD8 CD4 or CD8 CD8+ CD4+ CD8+ CD4+ CD25 Pro-T cell (double negative, DN) Pre-T cell (double negative, DN) Pro-T cell (double positive, DP) migration migration Surface markers Peripheral tissues Marrow Blood Blood Thymus RAG expression on Dβ-Jβ Vβ-Dβ-Jβ Vβ-Dβ-Jβ and Vα-Jβ TCR locus rearrangement Tc cell 8536d_ch10_221 8/27/02 1:37 PM Page 222 Mac 109 Mac 109:1254_BJN:Goldsby et al. / Immunology 5e: