Elsevier

Advances in Immunology

Volume 76, 2001, Pages 179-226
Advances in Immunology

Cell Death Control in Lymphocytes

https://doi.org/10.1016/S0065-2776(01)76020-8Get rights and content

Introduction

Lymphocyte apoptosis is crucial to proper immune function. It removes developing lymphocytes that fail to express an antigen receptor, thereby ensuring a functional repertoire of mature B and T cells, and it maintains tolerance toward self by eliminating lymphocytes with antigen receptors that recognize autoantigens. Apoptosis also regulates the size and duration of immune responses, activated lymphocytes being killed when an infection is cleared successfully. This chapter details the signaling pathways that are known to promote apoptosis as well as their impact on lymphocyte survival at different stages of development. Particular attention is paid to the roles of death receptors and members of the Bcl-2 protein family.

Section snippets

Apoptosis and the Role of Caspases

Cells within multicellular organisms have a genetically determined suicide program that can be triggered by a range of physiological signals and experimentally applied stress conditions. A family of intracellular aspartate-specific cysteine proteases called caspases activates the effector phase of this suicide program (Thornberry and Lazebnik, 1998). Activation of caspase zymogens leads to proteolytic cleavage of vital cellular constituents, which culminates in cell death. This cell death

Apoptosis Signaling by Death Receptors

For most apoptotic stimuli, the precise sequence of events that leads to multiple caspase zymogens being brought together by their adapter molecules is still being elucidated. One exception, in which the route to caspase activation has been determined, is during apoptosis signaled by certain death receptors (Figure 1). Forming a subset of the tumor necrosis factor receptor (TNF-R) family, death receptors are type I transmembrane proteins characterized by cysteine-rich repeats in their

Apoptosis Signaling through Apaf-1 and Caspase 9

While caspase 8 is the initial caspase to be activated in mammalian cells treated with FasL, TNF-α, and DR3L, other treatments may activate caspase 9 first (Figure 2). The role of caspase 9 as a critical initiator caspase is suggested by its long prodomain and by the phenotypes of mice lacking caspase 9 (Hakem et al., 1998, Kuida et al., 1998) or its adapter molecule Apaf-1 (Cecconi et al., 1998, Yoshida et al., 1998). Both mutant strains of mice exhibit neuronal hyperplasia attributed to a

Apoptosis and Its Regulation by Membersof the Bcl-2 Family

Proteins belonging to the Bcl-2 family are critical regulators of apoptosis (Adams and Cory, 1998). Members of this family have at least one of four Bcl-2 homology domains (BH1–4), and they can be divided into two groups based on their ability to either promote apoptosis (Bad, Bak, Bax, Bcl-xs, Bid, Bik, Bim/Bod, Blk, Bok, and Harakiri/DP5) or suppress it (A1/Blf-1, Bcl-2, Bcl-w, Bcl-xL, Boo/Diva, and Mcl-1) (Boise et al., 1993, Boyd et al., 1995, Chittenden et al., 1995, Farrow et al., 1995,

Transcriptional and Posttranslational Controlof Bcl-2 Family Members

Members of the Bcl-2 family can be regulated at the level of transcription. For example, transcripts for the pro-apoptotic protein DP5 are induced in neurons after nerve growth factor withdrawal (Imaizumi et al., 1997), whereas lymphocytes treated with mitogens increase transcription of anti-apoptotic genes. A1 induction in mitogen-stimulated B and T cells is dependent on the NF-κB transcription factor Rel (Grumont et al., 1999), while Bcl-xL is induced in T cells stimulated with cross-linking

Apoptosis and the Immune System

Apoptosis plays a prominent role in the development and homeostasis of the immune system. It contributes to (i) the generation of a functional repertoire of mature B and T cells by eliminating developing lymphocytes that fail to express an antigen receptor, (ii) tolerance toward self by removing lymphocytes with antigen receptors that recognize self antigens, and (iii) immune homeostasis by culling activated lymphocytes when an infection is cleared successfully (Strasser, 1995). The importance

T Cell Development—Apoptosis at the Pre-TCR Checkpoint

Mouse T lymphocytes of the T cell receptor (TCR)-α/β lineage develop in the thymus from bone marrow– or fetal liver–derived multipotential stem cells. Glycoproteins expressed at the cell surface and the rearrangement status of the TCR-α and TCR-β gene loci identify distinct stages of thymocyte differentiation (Figure 3). Early T cell progenitors (here called pro-T cells) are CD48 and can be subdivided into four populations according to expression of CD25 (interleukin 2 receptor [IL-2R] α

Positive and Negative Selection at thePre-T Stage of Development

Maturation to the pre-T stage coincides with TCR-α gene rearrangement (Petrie et al., 1993), and thymocytes expressing a complete TCR-α/β-CD3 complex become subject to immunological selection based on their TCR-α/β specificity (von Boehmer, 1994). Pre-T cells that lack a functional TCR fail to receive a survival signal and die by apoptosis, while cells bearing TCRs that can recognize self major histocompatibility complex (MHC) plus peptide antigens undergo positive selection. However, if the

T Cell Apoptosis in Peripheral Lymphoid Organs

Mature T cells in peripheral lymphoid organs require continued interaction with MHC molecules for their survival in vivo (Kirberg et al., 1997, Tanchot et al., 1997). Stimulation of the TCR may promote T cell survival by maintaining Bcl-2 protein levels within the cell because loss of Bcl-2, and not Bcl-xL, increases the spontaneous death of mature T cells in culture (Ma et al., 1995, Nakayama et al., 1993, Nakayama et al., 1994, Veis et al., 1993b). The different roles identified for the

The TNF-R Family and T Cell Proliferation

Members of the TNF-R family can promote cell proliferation (Alderson et al., 1993, Alderson et al., 1994, Grell et al., 1998, Yamada et al., 1997), and recent findings implicate death receptors in the proliferation of T cells. Studies using FADD-DN transgenic or FADD −/− T cells indicate that the cytoplasmic adapter FADD is required not only for apoptosis signaling by Fas but also for T cell proliferation (Newton et al., 1998, Zhang et al., 1998). FADD presumably engages molecules other than

B Cell Development—Apoptosis at the Pre-BCR Checkpoint

B cell development in the bone marrow resembles T cell development in that glycoproteins expressed at the cell surface and the rearrangement status of the immunoglobulin (Ig) heavy- and light-chain gene loci identify distinct stages of B cell differentiation (Figure 5). Early B cell progenitors (here called pro-B cells) are B220+CD43+c-Kit+ and their Ig heavy-chain gene loci are in the germline configuration. Rearrangement of the VH, DH, and JH variable heavy-chain gene segments and expression

Selection of Immature B Cells in the Bone Marrow

Expression of a pre-BCR, like expression of a pre-TCR during thymocyte development, promotes proliferation as well as survival and differentiation of developing B cells. After an estimated four to six cell divisions (Osmond, 1993), pre-B cells become small and rearrange their Ig light-chain genes (Benschop and Cambier, 1999). Nonproductive rearrangement of the κ and λ Ig light-chain genes yields a B cell that is unable to express surface IgM. Such B cells proba bly die by a Bcl-2–inhibitable

B Cell Apoptosis in Peripheral Lymphoid Organs

Some autoreactive B cells may be deleted in peripheral lymphoid organs (Figure 6). In mice that express a soluble form of HEL, for example, B cells specific for HEL are not deleted in the bone marrow and can be found in a functionally inactive state in peripheral lymphoid organs. These cells get deleted in vivo when they present antigen to HEL-specific CD4+8 T cells; FasL on the T cell surface engages Fas on the B cell surface, causing apoptosis (Rathmell et al., 1995). When Fas signaling is

Conclusion

Transgenic mice expressing inhibitors of apoptosis in their lymphocytes and mutant mice that lack apoptosis signaling molecules have provided significant insight into the mechanisms by which nonfunctional, dangerous, or effete lymphocytes are killed. They have provided evidence that death receptors and the Bcl-2 protein family regulate distinct pathways to apoptosis, and that these pathways are engaged in response to different physiological stimuli. However, the details of lymphocyte apoptosis

Acknowledgments

Work in our laboratory is supported by fellowships from the Leukemia Society of America, the University of Melbourne, and the Anti-Cancer Council of Victoria (Melbourne) and by grants from the National Health and Medical Research Council (Canberra), the Dr. Josef Steiner Cancer Research Foundation (Bern), the Cancer Research Institute (New York), and the Anti-Cancer Council of Victoria.

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