Why do defects in the Fas-Fas ligand system cause autoimmunity?

Why do defects in the Fas-Fas ligand system cause autoimmunity?

Special Lectures Why do defects in the Fas-Fas ligand system cause autoimmunity? Takashi Suda, PhD, a and Sigekazu Nagata, PhD a, b We have previousl...

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Special Lectures Why do defects in the Fas-Fas ligand system cause autoimmunity? Takashi Suda, PhD, a and Sigekazu Nagata, PhD a, b

We have previously isolated genes that encode Fas and Fas ligand, a receptor-ligand pair that mediates an apoptotic signal. We also have demonstrated that Ipr and gld mice, wellknown animal models of autoimmune disease are loss-offunction mutants of the Fas and Fas ligand genes, respectively. Patients with autoimmnne lymphoproliferative disorders have been found to bear mutations of the Fas gene. These findings indicate that the Fas-Fas ligand system plays an important role in the maintenance of self-tolerance among both humans and mice. During T-cell development, mouse T cells initially express Fas in the thymus and maintain their expression thereafter. Peripheral B cells usually express Fas at much lower levels than do T cells, but various stimuli enhance Fas expression on B cells. In contrast, among the lymphocyte subsets, only activated T cells and natural killer cells express readily detectable levels of Fas ligand. Reactivation of previously activated T cells through T-cell receptors induces apoptosis. This phenomenon (activation-induced cell death) is mediated by means Of the Fas-Fas ligand interaction. We recently discovered that peripheral naive T cells in mice are susceptible to Fas ligand but not to agonistic anti-Fas antibodies. To our surprise, engagement of T-cell receptors on naive T cells was shown to induce Fas ligand resistance. On the basis of these findings and other reports, we discuss how the breakdown of self-tolerance occurs as the result of defects in the Fas-Fas ligand system. (J Allergy Clin Immunol 1997;100:$97-101.)

Genes lpr and gld are spontaneous, autosomal recessive mutations that induce autoantibody production and lymphadenopathy because of accumulation of CD4 CD8= double-negative T cells in various strains of mice. These mutations also cause various autoimmune diseases in combination with certain background genes. The most severe diseases have been observed in combination with MRL background. MRL-Ipr/lpr mice show high levels of autoantibodies, including anti-DNA, anti-Sm antibodies and rheumatoid factor, and suffer from autoimmune nephritis, vascuiitis, and arthritis. As a result, half of mice die by the age of 5 months. This strain has been used as an animal model of systemic lupus erythematosus and rheumatoid arthritis. 1 Because wild-type MRL mice contract mild and delayed autoimmune diseases, and because C57BL/6-lpr/lpr mice do not contract apparent autoimmune diseases despite high rheumatoid From the aDepartmentof MolecularBiology,Osaka BioscienceInstitute; and bDepartmentof Genetics,OsakaUniversityMedicalSchool. Reprint requests:TakashiSuda, PhD, OsakaBioscienceInstitute,6-2-4 Furuedai, Suita-shi,Osaka 565 Japan. Copyright © 1997by Mosby-YearBook, Inc. 0091-6749/97$5.00 + 0 1/0/85404

Osaka, Japan

Abbreviations used AICD: LPS: mAb: MHC: mRNA: r-mFasL:

Activation-induced cell death Lipopolysaccharide Monoclonal antibody Major histocompatibility complex Messenger ribo•ucleic acid Recombinant soluble mouse FasL

factor levels, the Ipr or g[d mutation alone is not sufficient to induce these diseases. Nevertheless, the two genes are currently the best characterized genetic factors that contribute to autoimmune disease. The lpr and gld mutations are located on chromosomes 19 and 1, respectively, and are not complementary, because mice that carry heterozygous mutations of both genes are apparently healthy. The essentially identical abnormalities induced by nonallelic lpr and gld mutations have been explained by the discovery that these genes code for a receptor and its ligand, namely Fas and Fas ligand.2-4 Some patients with autoimmune diseases have been found to carry various loss-of-function mutations in the Fas gene. 5,6 Their symptoms resembled those of lpr mice, including lymphadenopathy and splenomegaly with accumulation of double-negative T cells and multiple autoimmune disorders such as hemolytic anemia and thrombocytopenia. The Fas protein is a 45 kilodalton type I transmembrane protein that belongs to the tumor necrosis factor and nerve growth factor family.7 Fas ligand is a type II transmembrane protein homologous to the members of the tumor necrosis factor family,s The main or only function of Fas is transduction of apoptotic signals from Fas ligand. During development, random rearrangement of antigen receptor genes in B and T cells inevitably produces potentially autoreactive cells. These autoreactive cells are believed to be Mlled by apoptosis either in the central lymphopoietic organs (thymus or bone marrow) or at the periphery. Thus it seems likely that Fas and Fas ligand regulate the apoptosis of lymphocytes, including autore~ictive cells, and that defects in this system lead to the breakdown of self-tolerance among both humans and mice. EXPRESSION OF FAS A N D FAS L I G A N D IN LYMPHOCYTE S U B P O P U L A T I O N S

The Fas protein is expressed by various tissues and cells.9 Lymphoid organs, such as the thymus, spleen, and lymph $97

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nodes express Fas (mRNA) at high levels. Flow cytometric analyses have revealed that most mouse thymocytes express high levels of Fas. w These include CD4+CD8 + double-positive, CD4+CD8 - and CD4-CD8 + single-positive, and CD3+DN cells, whereas C D 3 - D N pre-T cells show the lowest level of Fas expression. In the periphery, most T cells show significantly lower levels of Fas expression compared with single-positive thymocytes. Activation of these splenic single-positive T cells by anti-CD3 monoclonal antibody (mAb) enhances Fas expression. Freshly isolated splenic B cells have much lower levels of Fas expression than T cells. However, in situ hybridization analyses have revealed that germinal center B cells express high levels of Fas mRNA. 11 In vitro activation by lipopolysaccharide (LPS), anti-IgM or anti-CD40 antibodies induces Fas expression in B cells?2 Fas ligand m R N A expression has been detected in a limited number of organs, including the thymus, spleen, lymph nodes, lungs, small intestine, testis, and eye. 9,13 Among the various lymphocyte subsets, Fas ligand expression has been demonstrated in activated T cells, natural killer cells, and thymic NK 1.1 ÷ T cells.9, 14.15 One report stated that LPS-activated B cells express Fas ligand? 6 However, we have not found expression of Fas ligand in either resting or LPS-activated mouse B cells. Expression of Fas ligand in the testis and eye has been implicated in the phenomenon of immune privilege? 3, 17 I N V O L V E M E N T OF T AND B CELLS IN AUTOANTIBODY PRODUCTION Not only lymphadenopathy but also autoantibody production has been corrected in lpr mice by means of neonatal thymectomy or administration of anti-Thyl mAb. ~8-2° Thus T cells are essential for autoantibody production. Involvement of CD4 and CD8 T cells in lymphadenopathy and autoantibody production has been investigated by several approaches, including administration of antibodies against CD4 or CD8 and studies on mice lacking CD4, CD8, [32-microglobulin (hence class I major histocompatibility complex [MHC]), or Class II MHC genes. 21 -29 Treatment with an anti-CD4 mAb and lack of CD4 or class II MHC have been consistently shown to suppress autoantibody production, whereas anti-CD8 mAb treatment and lack of CD8 or class I MHC causes a reduction in lymphadenopathy or double-negative T cells. However, reports are inconsistent with respect to the involvement of CD4 T cells in lymphadenopathy and the role of CD8 T cells in autoantibody production. In some (but not all) studies, the occurrence of lymphadenopathy and autoantibody production have been segregated. Thus the simplest conclusion at present would be that CD4 T cells are essential for autoantibody production and that CD8 T cells are essential for lymphadenopathy, probably as a source of abnormal double-negative T cells. The necessity for lpr abnormality in T cells for autoantibody production was demonstrated by Eisenberg et al? ° In their experiments, lethally irradiated mice were reconstituted with a mixture of wild-type and lpr bone marrow

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cells. T cells and immunoglobulins derived from the lpr and wild-type bone marrow cells were designed to be differentiated by their Thy-1 and Igh allotypes. When lpr T cells were specifically removed with a mAb that recognized the Thy-1 allotype, lpr B cells could not produce autoantibody despite the presence of normal T cells. It also was demonstrated that intrinsic abnormalities of lpr B cells are essential for autoantibody production. Similar results were reported by Perkins et al. 31 These findings may indicate that lpr mutation disturbs self-tolerance of both T and B cells. THYMIC NEGATIVE SELECTION It has been well established that autoreactive T cells are first deleted in the thymus. This process is called negative selection, and it takes place at the doublepositive stage of thymic T-cell development. 3a In mice, Fas is expressed by double-positive immature T cells and single-positive mature T cells. Double-positive thymocytes are killed by anti-Fas mAb treatment, whereas single-positive cells are insensitive to the same m A b ? ° We have succeeded in producing recombinant soluble mouSe Fas ligand (r:mFasL) and have found that it kills single-positive thymocytesY However, the dose of rmFasL required to kill 50% of single-positive cells is ten times higher than the dose for double-positive cells. Because most of double-positive cells and single-positive cells are at a stage before and after negative selection, respectively, these results are consistent with the notion that the Fas-Fas ligand system plays a role in negative selection. Contrary to our expectation, however, most of the studies on negative selection among lpr or gld mice have concluded that thymic negative selection is normal among these mice. 34-36 Because we and others have found evidence that lpr is a leaky mutation, 37, 38 it was considered possible that the apparently normal thymic negative selection among Ipr mice is due to low-level Fas expression. This possibility has been formally excluded, because negative selection also is normal among Fasknockout mice, which completely lack a functional Fas gene? 9 These findings have demonstrated that the F a s Fas ligand system is not essential for thymic negative selection. However, it is still possible that thymic negative selection involves multiple systems and that the Fas-Fas ligand system is one of them. ACTIVATION-INDUCED CELL DEATH AND PERIPHERAL CLONAL DELETION Reactivation of previously activated T cells through the T-cell receptor CD3 complex in vitro induces apoptosis in a large population of these cells. This phenomenon has been called activation-induced cell death (AICD) or antigen-induced suicide. T cells sensitive to AICD include T-cell hybridomas or transformed T-cell lines, especially those maintained with IL-2 alone, and in vitro activated peripheral T cells. For example, when splenic T cells are activated with concanavalin A or anti-CD3 mAb and then expanded in IL-2 alone for several days followed by reactivation with anti-CD3

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mAb, more than 80% of the cells are killed by means of apoptosis. It has been shown that AICD is severely impaired among T cells derived from lpr and gld mice 4°'42 and those from autoimmune patients with Fas gene mutations. 5, 6 Administration of Staphylococcus enterotoxin B into wild-type mice initially induces expansion of responsive T cells (bearing V[38 T-cell receptor), which are subsequently deleted by means of apoptosis. This phenomenon is called peripheral clonal deletion and is believed to be an in vivo version of AICD; it is also diminished in lpr and gld mice. 43, 44 The physiologic role of this suicide mechanism is probably to restore homeostasis by means of removing most activated T cells except for a small number of memory T cells after control of infection has been achieved. These experimental systems have been considered as a model of peripheral tolerance by means of deletion of autoreactive T cells. However, the stimuli used in these studies have been nonspecific mitogens or, at best, exogenous antigens. If the latter hypothesis is true, it still remains to be explained how autoreactive and other T cells are differentiated in AICD. ANTIGEN RECEPTOR SIGNAL INDUCES FAS LIGAND RESISTANCE OF PERIPHERAL B AND T CELLS Rothstein et al. 12 reported that stimulation by antiIgM or anti-CD40 mAbs upregulates Fas expression on mouse B cells, but only the latter sensitizes them to Fas-mediated death. In addition, these authors found that B cells simultaneously stimulated by anti-IgM and anti-CD40 antibodies were protected from anti-Fas mAb-induced apoptosis. Rathmell et al. 45 reported that anergic autoreactive B cells are killed by helper T cells in a Fas ligand-dependent manner. It is likely that anergic B cells cannot transduce an antigen receptor signal that induces resistance against Fas-mediated apoptosis, so the situation may be similar to that of bystander B cells that encounter activated T cells. In mice, virtually all peripheral T cells express Fas but show no response to treatment with agonistic anti-Fas antibodies. 46 Thus it has been concluded that naive peripheral T cells are resistant to apoptotic signals from Fas. However, as with the single-positive thymocytes described earlier, we have found that freshly isolated T cells from the spleen or lymph nodes can be killed with r-mFasL. 33 We investigated how stimulation of naive T cells by means of T-cell receptor influences the susceptibility of naive T cells. A surprising finding was that activation of splenic T cells with anti-CD3 mAb induced temporary resistance of the T cells to subsequent treatment with r-mFasL. When similar experiments were performed with antibodies specific to a certain V[3 of T-cell receptor, T cells that expressed the corresponding V[3 were selectively rescued, whereas those that expressed other V[3s (bystander T cells) remained susceptible. Taken together, these results indicate that antigen receptor engagement induces resistance of both naive B and T cells to Fas-mediated apoptosis. Conversely, when

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FIG. 1. Two mechanisms of lymphocyte death mediated by Fas and FasL. A, Naive -I" cells initially activated by means of antigen (Ag) acquire resistance to Fas ligand-mediated apoptosis. However, on reactivation, T cells kill each other or themselves in a Fas and Fas ligand-dependent manner. B, Bystander T cells that encounter activated T cells are killed by the activated T cells through a mechanism that involves Fas ligand. Anergic autoreactive B cells are also susceptible to Fas ligand, probably because they cannot receive an antigen receptor signal that induces Fas ligand resistance. Open circles represent lymphocytes susceptible to Fas ligand. Shaded circles represent resistant cells. Crosses represent cell death.

bystander or anergic B or T cells encounter an inflammatory site, they would be killed by Fas ligand expressed in activated T cells; otherwise these cells may be irregularly activated by costimulatory signals such as CD40L or IL-2. Therefore, if the Fas-Fas ligand system is defective, bystander or anergic T and B cells, which potentially include autoreactive cells, might be accidentally activated. Such mechanisms may be involved in autoantibody formation. CONCLUSIONS We have described two types of lymphocyte death mediated by Fas and Fas ligand, that is, AICD and bystander/anergic lymphocyte death (Fig. 1). These two models are clearly different in that antigenic stimulation induces cell death in AICD, whereas the absence or impairment of antigenic stimulation results in cell death in the latter case. Defects of one or both of these lymphocyte cell death mechanisms in lpr and gld mice probably cause lymphadenopathy and autoantibody production. Because AICD operates only against previously activated T cells, it seems more suitable as a mechanism for controlling the turnover of T cells activated by foreign antigens. Accordingly, a defect of AICD may

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c a u s e a c c u m u l a t i o n o f a large n u m b e r o f activated T cells a n d r e s u l t in l y m p h a d e n o p a t h y . I n c o n t r a s t , t h e r e is n o e v i d e n c e to indicate t h a t a u t o l o g o u s a n t i g e n s i n d u c e A I C D in p e r i p h e r a l T cells. O n the o t h e r h a n d , t h e s e c o n d m o d e l s e e m s to b e t t e r e x p l a i n w h y defects in t h e F a s - F a s ligand s y s t e m c a u s e d e v e l o p m e n t o f a u t o r e a c tive T a n d B cells. P o t e n t i a l l y a u t o r e a c t i v e b y s t a n d e r or a n e r g i c cells m a y n o t o f t e n m e e t w i t h T cells activated by u n r e l a t e d antigens. H o w e v e r , this m a y b e t h e r e a s o n for t h e slow kinetics o f a u t o a n t i b o d y p r o d u c t i o n in

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