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maintenance of appropriate numbers ofvarious types of lymphocytes is extremely important to an effective immune system. One of the most important elements in this regulation is apoptosis mediated by the Fas/FasL ligand system. The following excerpts from medical histories show what can happen when this key regulatory mechanism fails.

Patient A: A woman, now 43, has had a long history of immunologic imbalances and other medical problems. By age 2, she was diagnosed with the Canale-Smith syndrome (CSS), a severe enlargement of such lymphoid tissues as lymph nodes (lymphadenopathy) and spleen (splenomegaly). Biopsy of lymph nodes showed that, in common with many other CSS patients, she had greatly increased numbers of lymphocytes. She had reduced numbers of platelets (thrombocytopenia) and, because her red blood cells were being lysed, she was anemic (hemolytic anemia). The reduction in numbers of platelets and the lysis of red blood cells could be traced to the action of circulating antibodies that reacted with these host components. At age 21, she was diagnosed with grossly enlarged pelvic lymph nodes that had to be removed. Ten years later, she was again found to have an enlarged abdominal mass, which on surgical removal turned out to be a half-pound lymph-node aggregate. She has continued to have mild lymphadenopathy and, typical of these patients, the lymphocyte populations of enlarged nodes had elevated numbers of T cells (87% as opposed to a normal range of 48%-67% T cells). Ex amination of these cells by flow cytometry and fluorescent antibody staining revealed an excess of double-negative T cells (see illustration below). Also, like many patients with Canale-Smith syndrome, she has had cancer, breast cancer at age 22 and skin cancer at ages 22 and 41.

Patient B: A man who was eventually diagnosed with Canale-Smith syndrome had severe lymphadenopathy and splenomegaly as an infant and child. He was treated from age 4 to age 12 with corti-costeroids and the immunosuppressive drug mercaptopurine. These appeared to help, and the swelling of lymphoid tissues became milder during adolescence and adulthood. At age 42, he died of liver cancer.

Normal control

Q 102

Normal control

Q 102


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102 CD4

Patient C: An 8-year-old boy, the son of patient B, was also afflicted with Canale-Smith syndrome and showed elevated T-cell counts and severe lymphadenopathy at the age of seven months. At age 2 his spleen became so enlarged that it had to be removed. He also developed hemolytic anemia and thrombocytopenia. However, although he continued to have elevated T-cell counts, the severity of his hemolytic anemia and thrombocytope-nia have so far been controlled by treatment with methotrexate, a DNA- synthesis-inhibiting drug used for immunosuppression and cancer chemotherapy.

Recognition of the serious consequences of a failure to regulate the number of lymphocytes, as exemplified by these case histories, emerged from detailed study of several children whose enlarged lymphoid tissues attracted medical attention. In each of these cases of Canale-Smith syndrome, examination revealed grossly enlarged lymph nodes that were 1-2 cm in girth and sometimes large enough to distort the local anatomy. In four of a group of five children who were studied intensively, the

Patient A

102 CD4

Flow-cytometric analysis of T cells in the blood of Patient A and a control subject. The relative staining by an anti-CD8 antibody is shown on the y axis and the relative staining by an anti-CD4 antibody appears on the x axis. Mature T cells are either CD4+ or CD8+. While almost all of the T cells in the control subject are CD4+ or CD8+, the CSS patient shows high numbers of double-negative T cells (43%), which express neither CD4 nor CD8. The percentage of each category of T cells is indicated in the quadrants. [Adapted from Drappa et al., 1996, New England Journal of Medicine 335:1643.]

80 400

Anti-Fas antibody (ng/ml)

Fas-mediated killing takes place when Fas is crosslinked by FasL, its normal ligand, or by treatment with anti-Fas antibody, which artificially crosslinks Fas molecules. This experiment shows the reduction in numbers of T cells after induction of apoptosis in T cells from patients and controls by crosslinking Fas with increasing amounts of an anti-Fas monoclonal antibody. T cells from the Canale-Smith patients (A and B) are resistant to Fas-mediated death. [Adapted from Drappa et al., 1996, New England Journal of Medicine 335:1643.]

spleens were so massive that they had to be removed.

Even though the clinical picture in Canale-Smith syndrome can vary from person to person, with some individuals suffering severe chronic affliction and others only sporadic episodes of illness, there is a common feature, a failure of activated lymphocytes to undergo Fasmediated apoptosis. Isolation and sequencing of Fas genes from a number of patients and more than 100 controls reveals that CSS patients are heterozygous (_/ôs+/~) at the fas locus and thus carry one copy of a defective fas gene. A comparison of Fas-mediated cell death in T cells from normal controls who do not carry mutant Fas genes with death induced in T cells from CSS patients, shows a marked defect in Fas-induced death (see illustration above). Characterization of the Fas genes so far seen in CSS patients reveals that they have mutations in or around the region encoding the death-inducing domain (the "death domain") of this protein (see illustration below). Such mutations result in the production of Fas protein that lacks biological activity but still competes with normal Fas molecules for interactions with essential components of the Fasmediated death pathway. Other mutations have been found in the extracellular domain of Fas, often associated with milder forms of CSS or no disease at all.

A number of research groups have conducted detailed clinical studies of CSS patients, and the following general observations have been made:

The cell populations of the blood and lymphoid tissues of CSS patients show dramatic elevations (5-fold to as much as 20-fold) in the numbers of lymphocytes of all sorts, including T cells, B cells, and NK cells. Most of the patients have elevated levels of one or more classes of immunoglobulin (hyper-gam maglobulin-emia).

Immune hyperactivity is responsible for such autoimmune phenomena as the production of autoantibodies against red blood cells, resulting in he-molytic anemia, and a depression in platelet counts due to the activity of anti-platelet auto-antibodies.

These observations establish the importance of the death-mediated regulation of lymphocyte populations in lymphocyte homeostasis. Such death is necessary because the immune response to antigen results in a sudden and dramatic increase in the populations of responding clones of lymphocytes and temporarily distorts the representation of these clones in the repertoire. In the absence of cell death, the periodic stimulation of lymphocytes that occurs in the normal course of life would result in progressively increasing, and ultimately unsustainable, lymphocyte levels. As the Canale-Smith syndrome demonstrates, without the essential culling of lymphocytes by apoptosis, severe and life-threatening disease can result.

Death domain

Death domain

<-Extracellular region-> <-Intracellular region->

Transmembrane region

Map offas locus. The fas gene is composed of 9 exons separated by 8 introns. Exons 1 -5 encode the extracellular part of the protein, exon 6 encodes the transmembrane region, and exons 7-9 encode the intracellular region of the molecule. Much of exon 9 is responsible for encoding the critical death domain. [Adapted from G. H. Fisher et al., 1995, Cell 81:935.]

molecular patterns that are found in certain pathogens but not in humans. Thus they may play a role as first lines of defense against certain pathogens, expressing effector functions that help control infection and secreting cytokines that promote an adaptive immune response by aß T cells and B cells.


■ Progenitor T cells from the bone marrow enter the thymus and rearrange their TCR genes. In most cases these thymocytes rearrange a p TCR genes and become ap T cells. A small minority rearrange 78 TCR genes and become 78 T cells.

■ The earliest thymocytes lack detectable CD4 and CD8 and are referred to as double-negative cells. During development, the majority of double-negative thymocytes develop into CD4+CD8~ ap T cells or CD4~CD8+ ap T cells.

■ Positive selection in the thymus eliminates T cells unable to recognize self-MHC and is the basis of MHC restriction. Negative selection eliminates thymocytes bearing high-affinity receptors for self-MHC molecules alone or self-antigen plus self-MHC and produces self-tolerance.

■ TH-cell activation is initiated by interaction of the TCR-CD3 complex with a peptide-MHC complex on an antigen-presenting cell. Activation also requires the activity of accessory molecules, including the coreceptors CD4 and CD8. Many different intracellular signal-transduction pathways are activated by the engagement of the TCR.

■ T-cells that express CD4 recognize antigen combined with a class II MHC molecule and generally function as TH cells; T cells that express CD8 recognize antigen combined with a class I MHC molecule and generally function as TC cells.

■ In addition to the signals mediated by the T-cell receptor and its associated accessory molecules (signal 1), activation of the Th cell requires a co-stimulatory signal (signal 2) provided by the antigen-presenting cell. The co-stimulatory signal is commonly induced by interaction between molecules of the B7 family on the membrane of the APC with CD28 on the TH cell. Engagement of CTLA-4, a close relative of CD28, by B7 inhibits T-cell activation.

■ TCR engagement with antigenic peptide-MHC may induce activation or clonal anergy. The presence or absence of the co-stimulatory signal (signal 2) determines whether activation results in clonal expansion or clonal anergy.

■ Naive T cells are resting cells (G0) that have not encountered antigen. Activation of naive cells leads to the generation of effector and memory T cells. Memory T cells, which are more easily activated than naive cells, are responsible for secondary responses. Effector cells are short lived and perform helper, cytotoxic, or delayed-type hypersensitivity functions.

■ The T-cell repertoire is shaped by apoptosis in the thymus and periphery.

■ 78 T cells are not MHC restricted. Most in humans bind free antigen, and most have the same specificity. They may function as part of the innate immune system.

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