《免疫学》（英文版） Chapter 02 Cells and organs of the Immune system

8536d_cho2024-056 8/5/02 4: 02 PM Page 29 mac79 Mac 79: 45_BW: Go dsby et al./Immunology se Cells and Organs of the Immune System CHAPTER 2 FIGURE 2-4 Apoptosis. Light micrographs of (a)normal t apoptotic thymocytes. [From B. A Osbome and S Smith, 1997, Jour- cytes( developing T cells in the thymus) and(b)apoptotic nal of NIH Research 9: 35: courtesy B. A. Osborne, University of Mass- cytes. Scanning electron micrographs of (c) normal and (d) achusetts at Amherst. J The expression of several genes accompanies apoptosis scriptional activation of the bcl-2 gene and overproduction in leukocytes and other cell types(Table 2-2). Some of the of the encoded Bcl-2 protein by the lymphoma cells. The proteins specified by these genes induce apoptosis, others resulting high levels of Bcl-2 are thought to help transform are critical during apoptosis, and still others inhibit apop- lymphoid cells into cancerous lymphoma cells by inhibit- tosis. For example, apoptosis can be induced in thymocytes ing the signals that would normally induce apoptotic cell by radiation, but only if the protein p53 is present; many death cell deaths are induced by signals from Fas, a molecule<( gulating the normal life span of various hematopoietic cell Bcl-2 levels have been found to play an important role in sent on the surface of many cells; and proteases known as caspases take part in a cascade of reactions that lead to lineages, including lymphocytes. A normal adult has about apoptosis. On the other hand, members of the bcl-2(B-cell 5 L of blood with about 2000 lymphocytes/mm for a total of lymphoma 2)family of genes, bcl-2 and bcl-XL encode pro- about 10 lymphocytes. During acute infection, the lym tein products that inhibit apoptosis. Interestingly, the first phocyte count increases 4-to 15-fold, giving a total lympho member of this gene family, bcl-2, was found in studies that cyte count of 40-50 X 10. Because the immune system rere concerned not with cell death but with the uncon- cannot sustain such a massive increase in cell numbers for an trolled proliferation of B cells in a type of cancer known as extended period, the system needs a means to eliminate un- B-lymphoma. In this case, the bcl-2 gene was at the break needed activated lymphocytes once the antigenic threat has point of a chromosomal translocation in a human B-cell passed. Activated lymphocytes have been found to express lymphoma. The translocation moved the bcl-2 gene into lower levels of Bcl-2 and therefore are more susceptible to the the immunoglobulin heavy-chain locus, resulting in tran- induction of apoptotic death than are naive lymphocytes or

Cells and Organs of the Immune System CHAPTER 2 29 The expression of several genes accompanies apoptosis in leukocytes and other cell types (Table 2-2). Some of the proteins specified by these genes induce apoptosis, others are critical during apoptosis, and still others inhibit apop￾tosis. For example, apoptosis can be induced in thymocytes by radiation, but only if the protein p53 is present; many cell deaths are induced by signals from Fas, a molecule pre￾sent on the surface of many cells; and proteases known as caspases take part in a cascade of reactions that lead to apoptosis. On the other hand, members of the bcl-2 (B-cell lymphoma 2) family of genes, bcl-2 and bcl-XL encode pro￾tein products that inhibit apoptosis. Interestingly, the first member of this gene family, bcl-2, was found in studies that were concerned not with cell death but with the uncon￾trolled proliferation of B cells in a type of cancer known as B-lymphoma. In this case, the bcl-2 gene was at the break￾point of a chromosomal translocation in a human B-cell lymphoma. The translocation moved the bcl-2 gene into the immunoglobulin heavy-chain locus, resulting in tran￾scriptional activation of the bcl-2 gene and overproduction of the encoded Bcl-2 protein by the lymphoma cells. The resulting high levels of Bcl-2 are thought to help transform lymphoid cells into cancerous lymphoma cells by inhibit￾ing the signals that would normally induce apoptotic cell death. Bcl-2 levels have been found to play an important role in regulating the normal life span of various hematopoietic cell lineages, including lymphocytes. A normal adult has about 5 L of blood with about 2000 lymphocytes/mm3 for a total of about 1010 lymphocytes. During acute infection, the lym￾phocyte count increases 4- to 15-fold, giving a total lympho￾cyte count of 40–50 109 . Because the immune system cannot sustain such a massive increase in cell numbers for an extended period, the system needs a means to eliminate un￾needed activated lymphocytes once the antigenic threat has passed. Activated lymphocytes have been found to express lower levels of Bcl-2 and therefore are more susceptible to the induction of apoptotic death than are naive lymphocytes or (a) (c) (b) (d) FIGURE 2-4 Apoptosis. Light micrographs of (a) normal thymo￾cytes (developing T cells in the thymus) and (b) apoptotic thymo￾cytes. Scanning electron micrographs of (c) normal and (d) apoptotic thymocytes. [From B. A. Osborne and S. Smith, 1997, Jour￾nal of NIH Research 9:35; courtesy B. A. Osborne, University of Mass￾achusetts at Amherst.] 8536d_ch02_024-056 8/5/02 4:02 PM Page 29 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

8536d_ch02_024-0568/5/02 4:02 PM Page 30 mac79 Mac 79: 45_BW: Godsby et al./Immunology 5e 30 PaRT I Introduction TABLE 2-2 Genes that regulate apoptosis Hematopoietic Stem Cells Can Be Enriched L. L. Weissman and colleagues developed a novel way of en Gene Function Role in apoptosis riching the concentration of mouse hematopoietic stem cells bc- Prevents apoptosi Inhibits which normally cor e less than 0.05% of all bone marrow cells in mice. Their approach relied on the use of an- Opposes bcl-2 Promotes tibodies specific for molecules known as differentiation bcl-XL(bck-Long) Prevents apoptosi Inhibits antigens, which are expressed only by particular cell types bcl-Xs(bcl-Short) Opposes bcl-X, They exposed bone-marrow samples to antibodies that had Protease Promotes been labeled with a fluorescent compound and were specific different ones) for the differentiation antigens expressed on the surface of fa duces apoptosis Initiates mature red and white blood cells( Figure 2-6). The labeled cells were then removed by flow cytometry with a luorescence- activated cell sorter(see Chapter 6). After each sorting, the remain ing cells were assayed to determine the number needed for memory cells. However, if the lymphocytes continue to be restoration of hematopoiesis in a lethally x-irradiated mouse activated by antigen, then the signals received during activa- As the pluripotent stem cells were becoming relatively more tion block the apoptotic signal. As antigen levels subside, so numerous in the remaining population, fewer and fewer does activation of the block and the lymphocytes begin to die cells were needed to restore hematopoiesis in this system. by apoptosis(Figure 2-5) Because stem cells do not express differentiation antigens Antigen Cytokine Tu cell l Bcl2 Activated b cell Cessation of, or inappropriate, Continued activating signals (e.g,cytokines, TH cells, antigen) Apoptotic cell Plasma cell B memory cell FIGURE2-5Regulation of activated B-cell numbers by apoptosis. making activated B cells more susceptible to programmed cell death Activation of B cells induces increased expression of cytokine recep- than either naive or memory B cells. A reduction in activating signals tors and decreased expression of Bcl-2. Because Bcl-2 prevents apop. quickly leads to destruction of excess activated B cells by apoptosis tosis, its reduced level in activated B cells is an important factor in Similar processes occur in T cells

30 PART I Introduction memory cells. However, if the lymphocytes continue to be activated by antigen, then the signals received during activa￾tion block the apoptotic signal. As antigen levels subside, so does activation of the block and the lymphocytes begin to die by apoptosis (Figure 2-5). Hematopoietic Stem Cells Can Be Enriched I. L. Weissman and colleagues developed a novel way of en￾riching the concentration of mouse hematopoietic stem cells, which normally constitute less than 0.05% of all bone￾marrow cells in mice. Their approach relied on the use of an￾tibodies specific for molecules known as differentiation antigens, which are expressed only by particular cell types. They exposed bone-marrow samples to antibodies that had been labeled with a fluorescent compound and were specific for the differentiation antigens expressed on the surface of mature red and white blood cells (Figure 2-6). The labeled cells were then removed by flow cytometry with a fluorescence￾activated cell sorter (see Chapter 6).After each sorting,the remain￾ing cells were assayed to determine the number needed for restoration of hematopoiesis in a lethally x-irradiated mouse. As the pluripotent stem cells were becoming relatively more numerous in the remaining population, fewer and fewer cells were needed to restore hematopoiesis in this system. Because stem cells do not express differentiation antigens TABLE 2-2 Genes that regulate apoptosis Gene Function Role in apoptosis bcl-2 Prevents apoptosis Inhibits bax Opposes bcl-2 Promotes bcl-XL (bcl-Long) Prevents apoptosis Inhibits bcl-XS (bcl-Short) Opposes bcl-XL Promotes caspase (several Protease Promotes different ones) fas Induces apoptosis Initiates FIGURE 2-5 Regulation of activated B-cell numbers by apoptosis. Activation of B cells induces increased expression of cytokine recep￾tors and decreased expression of Bcl-2. Because Bcl-2 prevents apop￾tosis, its reduced level in activated B cells is an important factor in B cell TH cell Antigen Cytokine receptor ↓ Bcl-2 ↑ Cytokine receptors Cessation of, or inappropriate, activating signals Continued activating signals (e.g., cytokines, TH cells, antigen) Plasma cell B memory cell Activated B cell Apoptotic cell Cytokines making activated B cells more susceptible to programmed cell death than either naive or memory B cells. A reduction in activating signals quickly leads to destruction of excess activated B cells by apoptosis. Similar processes occur in T cells. 8536d_ch02_024-056 8/5/02 4:02 PM Page 30 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

8536d_cho2024-056 8/5/02 4: 02 PM Page 31 mac79 Mac 79: 45_BW: Go dsby et al./Immunology se Cells and Organs of the Immune System CHAPTER 2 b) Lethally irradiated mouse (950 rads) 100 enriched cells ully enriched cells enriched cells Unenriched Restore hematopoiesis ANtibodies ouse lives to differentiation 10210310 Number of cells injected into lethally irradiated mouse 1×103 partly enriched cells ko o Differentiated React FIant bodies against Sca-1 FIGURE 2-6 Enrichment of the pluripotent stem cells from bone narrow.(a) Differentiated hematopoietic cells(white) are removed by treatment with fluorescently labeled antibodies( Fl-antibodies) specific for membrane molecules expressed on differentiated lin- ages but absent from the undifferentiated stem cells(S)and prog enitor cells(P). Treatment of the resulting partly enriched preparation fully enriched cells with antibody specific for Sca-1, an early differentiation antigen, re- moved most of the progenitor cells. M= monocyte; B= basopl N= neutrophil; Eo eosinophil; L= lymphocyte; E erythrocyte (b)Enrichment of stem-cell preparations is measured by their ability to restore hematopoiesis in lethally irradiated mice. Only animals in which hematopoiesis occurs survive. Progressive enrichment of cell stem cells is indicated by the decrease in the number of injected cells ore hematopoiesis needed to restore hematopoiesis. a total enrichment of about 1000- se lives fold is possible by this procedure known to be on developing and mature hematopoietic more than 10"nonenriched bone-marrow cells were needed cells, by removing those hematopoietic cells that express for restoration. Using a variation of this approach, H known differentiation antigens, these investigators were able Nakauchi and his colleagues have devised procedures that al to obtain a 50-to 200-fold enrichment of pluripotent stem low them to show that, in l out of 5 lethally irradiated mice, maining cells were incubated with various antibodies raised lymphoid lineages(Table 2-3/ sive rise to both myeloid and against cells likely to be in the early stages of hematopoiesis It has been found that CD34, a marker found on about One of these antibodies recognized a differentiation antigen of hematopoietic cells, while not actually unique to stem called stem-cell antigen 1 ( Sca-1). Treatment with this anti lls, is found on a small population of cells that contains body aided capture of undifferentiated stem cells and yielded stem cells. By exploiting the association of this marker wit a preparation so enriched in pluripotent stem cells that an stem cell populations, it has become possible to routinely quot containing only 30-100 cells routinely restored rich preparations of human stem cells. The administration of matopoiesis in a lethally x-irradiated mouse, whereas human-cell populations suitably enriched for CD34 cells

Cells and Organs of the Immune System CHAPTER 2 31 known to be on developing and mature hematopoietic cells, by removing those hematopoietic cells that express known differentiation antigens, these investigators were able to obtain a 50- to 200-fold enrichment of pluripotent stem cells. To further enrich the pluripotent stem cells, the re￾maining cells were incubated with various antibodies raised against cells likely to be in the early stages of hematopoiesis. One of these antibodies recognized a differentiation antigen called stem-cell antigen 1 (Sca-1). Treatment with this anti￾body aided capture of undifferentiated stem cells and yielded a preparation so enriched in pluripotent stem cells that an aliquot containing only 30–100 cells routinely restored hematopoiesis in a lethally x-irradiated mouse, whereas more than 104 nonenriched bone-marrow cells were needed for restoration. Using a variation of this approach, H. Nakauchi and his colleagues have devised procedures that al￾low them to show that, in 1 out of 5 lethally irradiated mice, a single hematopoietic cell can give rise to both myeloid and lymphoid lineages (Table 2-3). It has been found that CD34, a marker found on about 1% of hematopoietic cells, while not actually unique to stem cells, is found on a small population of cells that contains stem cells. By exploiting the association of this marker with stem cell populations, it has become possible to routinely en￾rich preparations of human stem cells. The administration of human-cell populations suitably enriched for CD34 cells Restore hematopoiesis, mouse lives E Eo L P L B E N Differentiated cells M N P S P React with Fl-antibodies against Sca-1 Lethally irradiated mouse (950 rads) Restore hematopoiesis, mouse lives 2 × 105 unenriched cells 1 × 103 partly enriched cells 30–100 fully enriched cells (a) E Eo L P L B E N M N P P S React with Fl-antibodies to differentiation antigens S P P Stem cell Progenitor cells P Restore hematopoiesis, mouse lives Survival rate, % 100 101 102 103 104 105 Number of cells injected into lethally irradiated mouse Fully enriched cells Partly enriched cells Unenriched cells (b) FIGURE 2-6 Enrichment of the pluripotent stem cells from bone marrow. (a) Differentiated hematopoietic cells (white) are removed by treatment with fluorescently labeled antibodies (Fl-antibodies) specific for membrane molecules expressed on differentiated lin￾eages but absent from the undifferentiated stem cells (S) and prog￾enitor cells (P). Treatment of the resulting partly enriched preparation with antibody specific for Sca-1, an early differentiation antigen, re￾moved most of the progenitor cells. M = monocyte; B = basophil; N = neutrophil; Eo = eosinophil; L = lymphocyte; E = erythrocyte. (b) Enrichment of stem-cell preparations is measured by their ability to restore hematopoiesis in lethally irradiated mice. Only animals in which hematopoiesis occurs survive. Progressive enrichment of stem cells is indicated by the decrease in the number of injected cells needed to restore hematopoiesis. A total enrichment of about 1000- fold is possible by this procedure. 8536d_ch02_024-056 8/5/02 4:02 PM Page 31 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

8536d_ch02_024-0569/6/02 9: 00 PM Page 32 maca Mac 85: 365_smm pldsby et al./ Immunology Se y TABLE 2.3 Reconstitution of hematopoeisis tant roles, engulfing and destroying microorganisms, pre- by HSCs senting antigens, and secreting cytokines. Number of Number of mice hoid Cell enriched HSCs reconstituted(%) Lymphocytes constitute 20%-40% of the body s white blood 9of41(21.9% cells and 99% of the cells in the lymph(Table 2-4). There are pproximately 10(range depending on body size and age 100-102)lymphocytes in the human body. These lym- 9of17(529% phocytes continually circulate in the blood and lymph and 10of11(90.9%) re capable of migrating into the tissue spaces and lymphoid 4of4(100%) organs, thereby integrating the immune system to a hig SOURCE: Adapted from M. Osawa, et al. 1996. Science 273: 242. The lymphocytes can be broadly subdivided into three populations--B cells, T cells, and natural killer cells--on the basis of function and cell-membrane components. Natural killer cells(NK cells) are large, granular lymphocytes that do he+"indicates that the factor is present on the cell mem- not express the set of surface markers typical of B or T cells brane)can reconstitute a patients entire hematopoietic sys- Resting B and T lymphocytes are small, motile, nonphago tem (see Clinical Focus) cytic cells, which cannot be distinguished morphologically. B A major tool in studies to identify and characterize the and T lymphocytes that have not interacted with antigen- human hematopoietic stem cell is the use of SCID(severe referred to as naive, or unprimed--are resting cells in the G ombined immunodeficiency)mice as in vivo assay systems phase of the cell cycle. Known as small lymphocytes, these for the presence and function of HSCs. SCID mice do not cells are only about 6 um in diameter; their cytoplasm forms have B and T lymphocytes and are unable to mount adaptive a barely discernible rim around the nucleus. Small lympho- immune responses such as those that act in the normal rejec ytes have densely packed chromatin, few mitochondria, and tion of foreign cells, tissues, and organs. Consequently, these a poorly developed endoplasmic reticulum and Golgi appa- animals do not reject transplanted human cell populations ratus. The naive lymphocyte is generally thought to have a containing HSCs or tissues such as thymus and bone mar- short life span. Interaction of small lymphocytes with anti ow. It is necessary to use immunodeficient mice as surrogate gen, in the presence of certain cytokines discussed later, in- or alternative hosts in human stem-cell research because duces these cells to enter the cell cycle by progressing from go there is no human equivalent of the irradiated ScId into G and subsequently into S, G2, and M(Figure 2-7a).As nice implanted with fragments of human thymus and bone they progress through the cell cycle, lymphocytes enlarge arrow support the differentiation of human hematopoietic into 15 um-diameter blast cells, called lymphoblasts; these tem cells into mature hematopoietic cells. Different subpop- cells have a higher cytoplasm: nucleus ratio and more or- ulations of CD34* human bone-marrow cells are injected ganellar complexity than small lymphocytes(Figure 2-7b) into these SCID-human mice, and the development of vari- Lymphoblasts proliferate and eventually differentiate into ous lineages of human cells in the bone-marrow fragment is effector cells or into memory cells. Effector cells function in bsequently assessed In the absence of human growth fac- various ways to eliminate antigen. These cells have short life tors,only low numbers of granulocyte-macrophage progen erythropoietin and others are administered along with LTABLE 2.4 Normal adult blood-cell counts CD34 cells, progenitor and mature cells of the myeloid lymphoid, and erythroid lineages develop. This system has Cell type Cells/mm enabled the study of subpopulations of CD34 cells and the Red blood cells 50×105 effect of human growth factors on the differentiation of var- Platelets 25×105 Leukocytes 73×103 Neutrophil Cells of the Immune Systen mphocyte Monocyte 1-6 Lymphocytes are the central cells of the immune system,re- sponsible for adaptive immunity and the immunologic at- tributes of diversity, specificity, memory, and self/nonself Basophil recognition. The other types of white blood cells play impor Gotowww.whfreeman.com/immunology@animation Cells and Organs of the Immune System

32 PART I Introduction (the “” indicates that the factor is present on the cell mem￾brane) can reconstitute a patient’s entire hematopoietic sys￾tem (see Clinical Focus). A major tool in studies to identify and characterize the human hematopoietic stem cell is the use of SCID (severe combined immunodeficiency) mice as in vivo assay systems for the presence and function of HSCs. SCID mice do not have B and T lymphocytes and are unable to mount adaptive immune responses such as those that act in the normal rejec￾tion of foreign cells, tissues, and organs. Consequently, these animals do not reject transplanted human cell populations containing HSCs or tissues such as thymus and bone mar￾row. It is necessary to use immunodeficient mice as surrogate or alternative hosts in human stem-cell research because there is no human equivalent of the irradiated mouse. SCID mice implanted with fragments of human thymus and bone marrow support the differentiation of human hematopoietic stem cells into mature hematopoietic cells. Different subpop￾ulations of CD34 human bone-marrow cells are injected into these SCID-human mice, and the development of vari￾ous lineages of human cells in the bone-marrow fragment is subsequently assessed. In the absence of human growth fac￾tors, only low numbers of granulocyte-macrophage progeni￾tors develop. However, when appropriate cytokines such as erythropoietin and others are administered along with CD34 cells, progenitor and mature cells of the myeloid, lymphoid, and erythroid lineages develop. This system has enabled the study of subpopulations of CD34 cells and the effect of human growth factors on the differentiation of var￾ious hematopoietic lineages. Cells of the Immune System Lymphocytes are the central cells of the immune system, re￾sponsible for adaptive immunity and the immunologic at￾tributes of diversity, specificity, memory, and self/nonself recognition. The other types of white blood cells play impor￾tant roles, engulfing and destroying microorganisms, pre￾senting antigens, and secreting cytokines. Lymphoid Cells Lymphocytes constitute 20%–40% of the body’s white blood cells and 99% of the cells in the lymph (Table 2-4). There are approximately 1011 (range depending on body size and age: ~1010–1012) lymphocytes in the human body. These lym￾phocytes continually circulate in the blood and lymph and are capable of migrating into the tissue spaces and lymphoid organs, thereby integrating the immune system to a high degree. The lymphocytes can be broadly subdivided into three populations—B cells, T cells, and natural killer cells—on the basis of function and cell-membrane components. Natural killer cells (NK cells) are large, granular lymphocytes that do not express the set of surface markers typical of B or T cells. Resting B and T lymphocytes are small, motile, nonphago￾cytic cells, which cannot be distinguished morphologically. B and T lymphocytes that have not interacted with antigen— referred to as naive, or unprimed—are resting cells in the G0 phase of the cell cycle. Known as small lymphocytes, these cells are only about 6 m in diameter; their cytoplasm forms a barely discernible rim around the nucleus. Small lympho￾cytes have densely packed chromatin, few mitochondria, and a poorly developed endoplasmic reticulum and Golgi appa￾ratus. The naive lymphocyte is generally thought to have a short life span. Interaction of small lymphocytes with anti￾gen, in the presence of certain cytokines discussed later, in￾duces these cells to enter the cell cycle by progressing from G0 into G1 and subsequently into S, G2, and M (Figure 2-7a). As they progress through the cell cycle, lymphocytes enlarge into 15 m-diameter blast cells, called lymphoblasts; these cells have a higher cytoplasm:nucleus ratio and more or￾ganellar complexity than small lymphocytes (Figure 2-7b). Lymphoblasts proliferate and eventually differentiate into effector cells or into memory cells. Effector cells function in various ways to eliminate antigen. These cells have short life TABLE 2-3 Reconstitution of hematopoeisis by HSCs Number of Number of mice enriched HSCs reconstituted (%) 1 9 of 41 (21.9%) 2 5 of 21 (23.8%) 5 9 of 17 (52.9%) 10 10 of 11 (90.9%) 20 4 of 4 (100%) SOURCE: Adapted from M. Osawa, et al. 1996. Science 273:242. TABLE 2-4 Normal adult blood-cell counts Cell type Cells/mm3 % Red blood cells 5.0 106 Platelets 2.5 105 Leukocytes 7.3 103 Neutrophil 50–70 Lymphocyte 20–40 Monocyte 1–6 Eosinophil 1–3 Basophil 1 Go to www.whfreeman.com/immunology Animation Cells and Organs of the Immune System 8536d_ch02_024-056 9/6/02 9:00 PM Page 32 mac85 Mac 85:365_smm:Goldsby et al. / Immunology 5e:

8536d_cho2024-056 8/5/02 4:02 PM Page 33 mac79 Mac 79: 45_BW: Go dsby et al./Immunology se Cells and Organs of the Immune System CHAPTER 2 Effector cell Go (i. e, plasma cell) Memory cell G Cycle repeats duces cell cycle entry ell division Small lymphocyte (T or B) Blast cell (T or B) Plasma cell(B) 6 um diameter 15 um diameter m URE2-7Fate of antigen-activated small lymphocytes. (a)a densed chromatin indicative of a resting cell, an enlarged lym- resting (naive or unprimed)lymphocyte resides in the Go phoblast(center) showing decondensed chromatin, and a plasma phase of the cell cycle. At this stage, B and T lymphocytes cannot be cell (night) showing abundant endoplasmic reticulum arranged in stinguished morphologically After antigen activation, a B or T cell concentric circles and a prominent nucleus that has been pushed to enters the cell cycle and enlarges into a lymphoblast, which under- a characteristically eccentric position. The three cells are shown goes several rounds of cell division and, eventually, generates effector different magnifications. [Micrographs courtesy of Dr.J. R. Goodman, cells and memory cells. Shown here are cells of the B-cell lineage. Dept of Pediatrics, University of Califomia at San Francisco. J (b) Electron micrographs of a small lymphocyte(left) showing con-

Cells and Organs of the Immune System CHAPTER 2 33 Lymphoblast S (DNA synthesis) Effector cell G0 (i.e., plasma cell) Memory cell G0 Small, naive B lymphocyte G0 Antigen activation induces cell cycle entry Cycle repeats Cell division M G1 (gene activation) (a) (b) Small lymphocyte (T or B) 6 µm diameter Blast cell (T or B) 15 µm diameter Plasma cell (B) 15 µm diameter G2 FIGURE 2-7 Fate of antigen-activated small lymphocytes. (a) A small resting (naive or unprimed) lymphocyte resides in the G0 phase of the cell cycle. At this stage, B and T lymphocytes cannot be distinguished morphologically. After antigen activation, a B or T cell enters the cell cycle and enlarges into a lymphoblast, which under￾goes several rounds of cell division and, eventually, generates effector cells and memory cells. Shown here are cells of the B-cell lineage. (b) Electron micrographs of a small lymphocyte (left) showing con￾densed chromatin indicative of a resting cell, an enlarged lym￾phoblast (center) showing decondensed chromatin, and a plasma cell (right) showing abundant endoplasmic reticulum arranged in concentric circles and a prominent nucleus that has been pushed to a characteristically eccentric position. The three cells are shown at different magnifications. [Micrographs courtesy of Dr. J. R. Goodman, Dept. of Pediatrics, University of California at San Francisco.] 8536d_ch02_024-056 8/5/02 4:02 PM Page 33 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: