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CD30 in Normal and Neoplastic Cells
Clinical Immunology Vol. 90, No. 2, February, pp. 157–164, 1999 Article ID clim.1998.4636, available online at http://www.idealibrary.com on
MOLECULE OF THE MONTH CD30 in Normal and Neoplastic Cells1 Roberto Chiarle, Antonello Podda, Gabriel Prolla, Jerry Gong, G. Jeanette Thorbecke, and Giorgio Inghirami Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York 10016
In 1982 Stein and coworkers identified a new molecule, CD30 (Ki-1), which is expressed by Reed–Sternberg (RS) cells of Hodgkin’s Disease (HD) (1). Although CD30 is not a specific RS cell marker, its characterization has assumed an important role not only in the differential diagnosis of HD, but also in the identification of a morphologically and clinically distinct type of large cell lymphoma, now designated as anaplastic large cell lymphoma (ALCL) (2). The cloning of human and murine CD30 and the utilization of genetically manipulated animal models have rapidly expanded our knowledge on its physiological role in lymphoid development and differentiation. The goal of this review is to present an overview of this rapidly evolving field and discuss the role of CD30 in normal and neoplastic lymphoid cells. © 1999 Academic Press STRUCTURAL PROPERTIES OF THE CD30 MOLECULE
CD30 is a member of the tumor necrosis factor receptor (TNF-R) superfamily, which comprises more than 10 different members (3). These molecules, which share a variable degree of homology, are characterized by a series of three or four cysteine-rich pseudorepeats in their extracytoplasmic region (3, 4). The protein analysis of human CD30 demonstrates that this molecule has an 18-residue leader peptide, followed by a 365 aa extracytoplasmic domain, a 24 aa transmembrane region, and a cytoplasmic domain of 188 aa. The human CD30 extracytoplasmic domain can be divided into six cysteine-rich motifs of approximately 40 aa that contain six cysteines with the exception of motif 1B and 3B, which are truncated (5). A hinge region of approximately 50 aa, which contains multiple serine, threonine, and proline residues and is O-glycosylated (6), connects the two cysteine-rich domains. There are two sites for N-linked glycosylation (7). The intracellular domain of human CD30 is long and its sequence diverges significantly from the intracellu1 These studies were partially supported by Grants CA-64033 and CA-14462 to G.I. and G.J.T., respectively.
lar sequences of all other TNF-R family members (4). Within this domain, two short peptide sequences, PHYPEQET and MLSVEEEGKE, shared by other members of this family, have recently been demonstrated to bind the TNF-R-associated factors (TRAF)1, 2, 3, and 5 (8 –10). A novel domain (D1), upstream of the D2 and D3 domains where TRAF1, 2, 3, and 5 bind, and capable of activating NF-kB, has recently been identified (11). Within the intracellular domain a conserved motif for ATP-binding (GxGxxG) found in many protein kinases, is also present. Finally, potential phosphorylation sites for tyrosine kinase and serine/ threonine kinases are located in the extracellular and intracellular domains, respectively. The majority of the monoclonal antibodies (Mabs) against human CD30 recognize epitopes within the extracytoplasmic domain. Crosslinking CD30 via these epitopes may result in (a) the proteolytic degradation of the protein, through a metalloprotease-dependent pathway and the ultimate release of sCD30 products into the extracellular compartment (12, 13), or (b) its functional activation (14 –16). The latter results in the engagement of multiple intracellular molecules leading to the firing of intracellular transduction pathway(s) (10, 11, 17). However, not all the anti-CD30 Mabs can cause these effects and many of them are unable to produce any detectable biological changes (18, 19). Northern blot analysis demonstrates the expression of multiple RNA species corresponding to the full length and alternatively spliced products, resulting in the translation of a putative 64-kDa protein, which, due to its rich cysteine content, migrates as a 84-kDa protein, and in shorter products, encoding only the CD30 intracellular domain (20). The full-length protein is heavily glycosylated within the Golgi apparatus (120 kDa). The precise molecular interactions between CD30 and its receptor ligand, CD30L, are unclear. However, the crystal structures of other TNF-R family members demonstrate that ligands interact with their corresponding receptors as trimers. These interactions are
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largely mediated by the cysteine-pseudorepeats of the receptor which fold tightly together, forming intimate longitudinal contacts with the neighbors. Each trimer ligand complex interacts with three receptor chains (21). Powell et al. have recently demonstrated that chimeric human CD30L-CD8a molecules spontaneously trimerize and can effectively engage CD30 receptors (22). The mechanism leading to this trimerization is not clear, but the generation of disulfide bonds between the extracellular domain of different CD30L molecules may result in their aggregation. The mouse CD30 is highly homologous to the human; however, it is 97 aa shorter, lacking one of the extracellular cysteine-rich domains. The full-length cDNA encodes a protein of 498 aa consisting of an 18 aa leader peptide sequence, 263 aa extracellular domain, 27 aa transmembrane domain, and 190 aa intracellular region (23). The putative molecular mass of the protein is 52 kDa, but after glycosylation it migrates at 110 kDa (24). Potential N-glycosylation, protein kinase C, and casein kinase II phosphorylation sites, similar to those of the human CD30, are also present. Two Mabs recognizing the extracellular domain of the murine CD30 have been generated (23). Both are capable of efficiently activating CD30 (23–25). The rat CD30 has also been cloned recently (26). The deduced rat CD30 protein consists of 493 aa with a relative high homology, particularly within the intracellular terminal C-terminus region, with the human and mouse proteins. Two mRNA transcripts, corresponding to those found in human CD301 cells of 3.4 and 2.3 kb, are transcribed in T-cells and in lung tissue, respectively. CD30 EXPRESSION IN NORMAL CELLS
CD30 is preferentially expressed by activated lymphoid cells. In normal peripheral lymphoid organs, CD301 cells are seen within the parafollicular areas and in the rim of the follicular centers. These interfollicular B and T cells have abundant cytoplasm and evident nucleoli, are proliferating (27), and often coexpress Bcl-6 (28). In addition, CD301 centroblasts are found within germinal centers (2). CD301 cells are also identified in the medulla of the thymus, frequently around the Hassal’s corpuscles, which express detectable CD30L (29). Despite readily evident mRNA transcription in the thymus (23, 24), surface CD30 expression on thymocytes is virtually undetectable. In contrast, using indirect immunofluorescence, a variable percentage (3–31%) of human peripheral blood lymphocytes have been demonstrated to express surface CD30. Many of these cells belong to the CD8 subset and produce IFN-g and IL-4 (30). In addition to B and T lymphocytes, lung macrophages (20), activated
NK cells (31), endothelial cells (32), and decidual cells (33) also express CD30 to variable extents. In vitro, CD30 expression on T cells can be achieved after mitogen activation, antigen receptor crosslinking, and as a result of viral infection (1, 23, 25, 34). Maximal expression is obtained within 3– 6 days, depending on the cell system used. Surface CD30L and CD30 expression have different kinetics and differ with respect to the T cell type in which they are preferentially expressed. After activation, CD30 is expressed by the majority of murine CD81 and a minority of CD41 cells. In contrast, CD30L is primarily expressed on non T cells and CD41 T cells and to a lesser extent on CD81 T cells (23). Activated human CD81, more frequently than CD41 cells, express high CD30 and belong exclusively to the CD45RO1 memory subset of T cells (34). The role of CD30 in these memory cells is unclear, particularly in consideration of the fact that in CD302/2 mice T cell memory responses appear normal (35). Activation via anti-CD3 alone generally induces weak CD30 expression. However, IL-2 enhances CD30 expression in human and murine T cells (25, 34). While endogeneous IL-4 allows and sustains (25, 36) its expression, CD30 is down-regulated by IFN-g (36). AntiCD28 causes upregulation of CD30 expression even in the absence of IL-4 (25, 37). In contrast, stimulation via CD30 results in the downregulation of CD28 (18). CD30 is preferentially and/or constitutively expressed by T cells producing Th2-type cytokines. Th0 and Th1 cells do not express CD30, or may only transiently express it after in vitro activation (38 – 41). However, CD30 expression is not an absolute and exclusive prerogative of Th2 clones. In fact, after in vitro activation by Ags that elicit either Th0, or Th1 and 2-type responses, CD301 T cell clones, producing IFN-g and/or other lymphokines, can be established (42). Finally, in mycobacterial infections, an elevated number of CD301 IFN-g producing T cells are found in affected lungs (43). It has been reported that in normal and in HIV-positive individuals the relatively large population of CD81CD301 T cells are able to produce not only IFN-g, but also IL-5 (44) and IL-4 (38). Interestingly, IFN-g production is controlled by IL-12 only in CD301 but not CD302 T cells (45). Overall, the findings indicate, however, that Th2 cells and IL-4 production are strongly linked with CD30 expression. Many investigators have demonstrated a correlation between the presence of CD301 T cells and of soluble CD30 with Th2-response-associated clinical entities (40). This is, perhaps, the case in the Omen syndrome. These children, who exhibit severe immunodeficiency, characterized by clinical and laboratory features reminiscent of Th2 responses, have numerous CD301 cells within their lymphoid tissues and in the peripheral blood (46). CD301 cells and/or high serum CD30 levels, particularly during the acute phase of the disease, are also
CD30 IN NORMAL AND NEOPLASTIC CELLS
found in patients with systemic lupus erythematosus (47), rheumatoid arthritis (48), Wegener’s granulomatosis (49), systemic sclerosis (50), and atopic dermatitis (51, 52). Lymphoid cells carrying viral EBV, HTLV-I (1), or Saimiri virus (53) genomes express high levels of CD30. Whether this expression is directly due to viral transactivation of CD30 and/or simply correlates with cell activation and proliferation is unclear. However, it should also be noted that, in vivo, a higher number of CD301 cells and/or high levels of circulating soluble CD30 are often detected after viral infection. In the case of acute infectious mononucleosis, CD301 B and T cells are often positive for EBV and display significant morphological atypia. Patients positive for hepatitis C (54), hepatitis B (55), or HIV (56) often have high serum CD30. High titers of CD30 have been correlated with the peak concentration of HIV Ag in acute primary HIV infection and the rate of viral replication (56, 57). In fact, soluble CD30 and TNF-a levels are useful parameters in predicting the clinical course of primary HIV infections (58). A contributing factor to enhanced viral production could be the activation of CD30 on CD41 T cells via CD30L on other cells, as it results in the activation of NF-kB binding to sites in the HIVLTR regions, thereby enhancing viral transcription (19, 59, 60). CD30 EXPRESSION IN NEOPLASTIC CELLS
Overexpression of CD30 has been documented not only in lymphoproliferative disorders, but also in rare solid tumors, including embryonal carcinomas (61, 62) and some seminomas (63). As in the case of CD301 lymphoproliferative disorders, receptor–ligand interaction may function in the autocrine growth regulation of embryonal carcinoma cells (64). However, CD30 expression has become crucial in characterization of human lymphoproliferative disorders not only to identify HD but also to recognize ALCL and CD301 nonHodgkin Lymphoma (NHL). In the case of classical (nodular sclerosis, mixed cellularity, and lymphocyte depletion) HD, the large majority of Reed–Sternberg (RS) cells are positive for CD30 (65). In contrast, in the lymphocyte predominant (LP) variant of HD the neoplastic cells are weak to moderately positive (66, 67). Extensive studies of the Ig gene products of RS cells have confirmed that these neoplastic cells often exhibit VDJ rearrangement as well as somatic mutation and, therefore, are of B-cell origin (68 –71). Their normal cellular counterpart is still controversial, but they most likely represent germinal center B cells, possibly caught in the process of receptor editing. This hypothesis is supported by the fact that in LP and in some classical HD, the RS cells express Bcl-6 (72), a protein that is highly expressed by germinal center cells and by
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cells which have passed through the germinal center (73, 74). In HD, serum levels of CD30 are elevated in the majority of untreated patients and correlate with clinical features, such as stage, symptoms, and tumor burden, being of prognostic significance (75–77). Similarly, in ALCL very high levels of serum CD30 can be observed (78). Finally, considering that in normal individuals the percentage of CD301 cells is quite small, the expression of CD30 in tumor cells may be used to specifically target chemotherapeutic agents against CD301 neoplastic cells. This approach has been successfully used in vitro (79) and in animal models (80). The molecular mechanisms regulating the expression of CD30, as well as the possible alterations in such pathways in RS cells, are still largely unclear. One possibility is that the expression of CD30 on RS cells may be related to the stage of differentiation of the corresponding normal cell from which they are derived. If RS cells represent the transformation of germinal center cells, it is important to consider that CD301 B centroblasts are present within normal germinal centers and that CD30 expression may be related to a particular stage of B cell differentiation (81). On the other hand, RS cells often carry viral EBV genomic sequences (82, 83). In approximately 50% of all HD, the RS cells are EBV positive and EBV infection has been demonstrated to induce CD30 gene transcription and protein expression (84). Although CD30 is not a specific RS cell marker, analysis of its expression has assumed an important role in the differential diagnosis of HD. Moreover, the systematic utilization of immunohistochemical techniques has permitted the identification of a previously unrecognized category of NHL, now designated ALCL, which is of T cell origin and CD301. Before the discovery of CD30, these lymphomas were not recognized as a distinct clinicopathologic entity and, instead, were variously considered to be different NHL or other nonlymphoid malignancies. Finally, ALCL should be distinguished from other CD301 NHL. Among the CD301 T cell lymphomas, which in general have a better prognosis compared to the CD301 B-NHL (85), those of the skin even exhibit spontaneous regression (86). FUNCTIONAL ROLE OF CD30 IN NORMAL AND NEOPLASTIC CELLS
The function of CD30 is largely unknown. Emerging information indicates that the activation of CD30 may provide positive or negative signals. These pleiotropic effects of CD30 have been primarily elucidated in vitro. It was found that CD30 activation may result in enhanced cell proliferation, cell growth arrest, or apoptosis (15, 87). CD30 activation has been reported to increase the proliferation of “T-cell-like,” but not “B-cell-like” CD301 HD cell lines (15). The precise
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mechanisms regulating these processes are unclear. However, crosslinking of CD30 expressed by HDderived cell lines results in enhanced IL-6, TNF, and lymphotoxin (LT)-a release (37, 88), all cytokines which can trigger TNF-R1 (p75) and IL6-R expressed by RS cells and modulate their growth (89). Crosslinking of CD30 and CD40 results in the enhanced expression and secretion of ICAM-1 (CD54) and B7-1 (CD80) (37, 90). Many cell lines derived from mature B cells do not change their growth patterns nor are blocked after CD30 activation (15). On the other hand, crosslinking of CD30 on EBV-infected B cells, but not on Burkitt’s cell lines, enhances their Ig secretion. Finally, in Tlymphoblastoid cells and ALCL lines, CD30 crosslinking results in a block of proliferation or in cell death (15, 22). Using a chimeric CD8/CD30 molecule, Lee et al. have demonstrated that apoptosis of T cell hybridomas requires the multimerization of CD30 cytoplasmic domains and concomitant signal(s) via TCR (87). Signal transductions in Jurkat cells via CD30 also requires the presence of the TCR/CD3 complex (34). These findings indicate that CD30 acts as a coreceptor, possibly modulating the effect of the antigen receptor complex. More recently, the cloning of the CD30 and CD30L genes has opened new investigational avenues such as the generation of CD30 transgenic (Tg) (24) and knockout (2/2) mice (35). Using our CD30 Tg mice, in which expression of CD30 was directed to the T cells by use of the CD4 promoter, we demonstrated that concomitant engagement of CD3 and CD30 on thymocytes results in enhanced cell death, compared to that achieved by anti-CD3 alone (24). Moreover, we found that crosslinking of overexpressed CD30 alone enhanced spontaneous apoptosis. CD30 overexpression also enhances the deletion of Vb81CD41CD82 thymocytes by low doses of SEB and of CD41CD81 DO11.10 Tg thymocytes expressing low-intermediate antiovalbumin TCR by specific peptides (24). These findings support the hypothesis that CD30 may be involved in negative selection in the thymus. This is in agreement with data derived from CD302/2 mice (35). These animals have large thymi and normal lymphoid peripheral organs and show an impaired negative selection in vitro and in vivo as demonstrated in a/b or g/d TCR-transgenic animals. However, none of these animal models have thrown much light on the role of CD30 in mature peripheral T cells. Purified CD301 Tg T cells crosslinked with anti-CD30 Mabs are activated and enter cell cycle replication. Furthermore, synergistic stimulation occurs between submitogenic anti-CD3 concentrations and anti-CD30 (24). Similar results were obtained with BALB/cJ cells in which CD30 expression was induced by anti-CD3 and anti-CD28 in the presence of IL-4 (25). Thus, CD30 can act as a costimula-
tory molecule in synergism with the CD3/TCR complex. MEDIATION OF CD30 SIGNALING
The CD30 engagement by its corresponding ligand and/or by functional anti-CD30 Mab induces a rapid series of changes largely mediated by the interactions of its cytoplasmic portion with multiple transducer proteins (Fig. 1). Four TRAF molecules, 1, 2, 3, and 5, can bind independently and/or as a complex to the cytoplasmic tail of CD30. TRAF1 and 2, 3, and 5 bind to short peptide sequences located at 462– 466, 480 – 485, and 464 – 470, respectively (8 –10). Recently a new region defined as the D1 domain has also been shown to be involved in a pathway that leads to activation of NF-kB (11). In in vitro systems, the activation of CD30 has been associated with NF-kB activation through TRAF2-dependent and independent pathways (11, 17). These findings are indirectly supported by studies on Tg mice overexpressing a dominant negative form of TRAF2 (91) or on TRAF22/2 (92) mice, demonstrating that, in absence of functional TRAF2, NF-kB activation can still be achieved by TNF-R1 activation, even though c-jun activation is impaired. It should be noted, however, that CD30 crosslinking on thymocytes from our CD30 Tg mice does not appear to lead to any activation of NF-kB or c-jun pathways (24). However, using the CD30 Tg mice, we could demonstrate that the apoptotic pathway in Tg thymocytes is mediated by caspases 1 and 3, since it was blocked by specific peptides. Moreover, Bcl-2 plays an important role, considering that in double transgenic mice for CD30 and Bcl-2, the CD30-induced apoptosis was completely inhibited (24). With respect to the pleiotropic effects of anti-CD30, additional factors should be considered, as different CD30-mediated responses could depend on the concomitant expression of other molecules. The differential expression of proteins such as Nur77 (93), TRIP, and TRAF1 (94) in different cells and/or at different stages of cell differentiation, may control and modulate different mediators and/or pathways, thereby influencing the overall results obtained with agents inducing apoptosis under some, but not all, circumstances. Finally, the concomitant engagement of CD30 and other molecules, including TNF-R, can result in the modulation of shared transduction molecules which may result in the modulation or inhibition of specific pathways. CD30 activation results in an enhanced degradation of TRAF2 (96), thus the effects resulting from the coactivation of molecules acting via TRAF2 may be abolished or preferentially shifted toward alternative pathways (91, 95). Germinal center and/or activated B cells, when engaged with anti-CD40, undergo Ig class switch and exhibit downregulation of CD30 expression. How-
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also express CD30L (101). These findings suggest that CD30 and CD30L, contrary to other members of the TNF superfamily, can elicit multidirectional signals leading to the activation of the interacting cellular elements. REFERENCES
FIG. 1. CD30 and signal transduction pathway. The crosslinking of CD30 may result in the activation of different pathways. In thymocytes CD30 crosslinking leads to the activation of caspase 1 and 3 and apoptosis. This pathway may be blocked by cIAP and is bcl-2 dependent. In the case of mature T cells, CD30-CD30L complexes result in the engagement of TRAF molecules which mediate the activation of NF-kB. TRIP inhibits the TRAF-mediated cell activation/growth, promoting indirectly proapoptotic signals.
ever, if CD40 and CD30 are simultaneously engaged CD40-induced germline transcription of the e gene is consistently inhibited (81) and switching is effectively hampered (96). It was originally speculated that CD30, as other members of the TNF-R superfamily, would be the only partner of the receptor–ligand pair, capable of activating a downstream cascade. Recently, it has been suggested that, in the case of CD30/CD30L complexes, this model may be too simplified. In fact, when CD30L is engaged by soluble CD30-Ig it can, in the presence of IL-2, IL-4, or IL-5, induce mouse B cell differentiation and Ig production (97). In addition, the activation of CD30L can elicit the production of IL-8 and a rapid oxidative burst by freshly isolated neutrophils. Finally, anti-CD30L Mab can induce IL-6 production in CD30L1 T lymphocytes (98). These findings are interesting in view of the complex cellular interactions and cytokine-mediated effects in HD (99). In classical HD, neutrophils and eosinophils are characteristically present, representing an important and often specific component of this lesion. It is of interest that in HD, these cells express high levels of surface CD30L and that IL-5, IL-3, and GM-CSF, which can all be produced by RS cells (14), are able to enhance CD30L expression on purified eosinophils from normal subjects (100). In addition, T cells within the HD lesion
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Received September 9, 1998; accepted October 1, 1998
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MOLECULE OF THE MONTH CD30 in Normal and Neoplastic Cells1 Roberto Chiarle, Antonello Podda, Gabriel Prolla, Jerry Gong, G. Jeanette Thorbecke, and Giorgio Inghirami Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York 10016
In 1982 Stein and coworkers identified a new molecule, CD30 (Ki-1), which is expressed by Reed–Sternberg (RS) cells of Hodgkin’s Disease (HD) (1). Although CD30 is not a specific RS cell marker, its characterization has assumed an important role not only in the differential diagnosis of HD, but also in the identification of a morphologically and clinically distinct type of large cell lymphoma, now designated as anaplastic large cell lymphoma (ALCL) (2). The cloning of human and murine CD30 and the utilization of genetically manipulated animal models have rapidly expanded our knowledge on its physiological role in lymphoid development and differentiation. The goal of this review is to present an overview of this rapidly evolving field and discuss the role of CD30 in normal and neoplastic lymphoid cells. © 1999 Academic Press STRUCTURAL PROPERTIES OF THE CD30 MOLECULE
CD30 is a member of the tumor necrosis factor receptor (TNF-R) superfamily, which comprises more than 10 different members (3). These molecules, which share a variable degree of homology, are characterized by a series of three or four cysteine-rich pseudorepeats in their extracytoplasmic region (3, 4). The protein analysis of human CD30 demonstrates that this molecule has an 18-residue leader peptide, followed by a 365 aa extracytoplasmic domain, a 24 aa transmembrane region, and a cytoplasmic domain of 188 aa. The human CD30 extracytoplasmic domain can be divided into six cysteine-rich motifs of approximately 40 aa that contain six cysteines with the exception of motif 1B and 3B, which are truncated (5). A hinge region of approximately 50 aa, which contains multiple serine, threonine, and proline residues and is O-glycosylated (6), connects the two cysteine-rich domains. There are two sites for N-linked glycosylation (7). The intracellular domain of human CD30 is long and its sequence diverges significantly from the intracellu1 These studies were partially supported by Grants CA-64033 and CA-14462 to G.I. and G.J.T., respectively.
lar sequences of all other TNF-R family members (4). Within this domain, two short peptide sequences, PHYPEQET and MLSVEEEGKE, shared by other members of this family, have recently been demonstrated to bind the TNF-R-associated factors (TRAF)1, 2, 3, and 5 (8 –10). A novel domain (D1), upstream of the D2 and D3 domains where TRAF1, 2, 3, and 5 bind, and capable of activating NF-kB, has recently been identified (11). Within the intracellular domain a conserved motif for ATP-binding (GxGxxG) found in many protein kinases, is also present. Finally, potential phosphorylation sites for tyrosine kinase and serine/ threonine kinases are located in the extracellular and intracellular domains, respectively. The majority of the monoclonal antibodies (Mabs) against human CD30 recognize epitopes within the extracytoplasmic domain. Crosslinking CD30 via these epitopes may result in (a) the proteolytic degradation of the protein, through a metalloprotease-dependent pathway and the ultimate release of sCD30 products into the extracellular compartment (12, 13), or (b) its functional activation (14 –16). The latter results in the engagement of multiple intracellular molecules leading to the firing of intracellular transduction pathway(s) (10, 11, 17). However, not all the anti-CD30 Mabs can cause these effects and many of them are unable to produce any detectable biological changes (18, 19). Northern blot analysis demonstrates the expression of multiple RNA species corresponding to the full length and alternatively spliced products, resulting in the translation of a putative 64-kDa protein, which, due to its rich cysteine content, migrates as a 84-kDa protein, and in shorter products, encoding only the CD30 intracellular domain (20). The full-length protein is heavily glycosylated within the Golgi apparatus (120 kDa). The precise molecular interactions between CD30 and its receptor ligand, CD30L, are unclear. However, the crystal structures of other TNF-R family members demonstrate that ligands interact with their corresponding receptors as trimers. These interactions are
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largely mediated by the cysteine-pseudorepeats of the receptor which fold tightly together, forming intimate longitudinal contacts with the neighbors. Each trimer ligand complex interacts with three receptor chains (21). Powell et al. have recently demonstrated that chimeric human CD30L-CD8a molecules spontaneously trimerize and can effectively engage CD30 receptors (22). The mechanism leading to this trimerization is not clear, but the generation of disulfide bonds between the extracellular domain of different CD30L molecules may result in their aggregation. The mouse CD30 is highly homologous to the human; however, it is 97 aa shorter, lacking one of the extracellular cysteine-rich domains. The full-length cDNA encodes a protein of 498 aa consisting of an 18 aa leader peptide sequence, 263 aa extracellular domain, 27 aa transmembrane domain, and 190 aa intracellular region (23). The putative molecular mass of the protein is 52 kDa, but after glycosylation it migrates at 110 kDa (24). Potential N-glycosylation, protein kinase C, and casein kinase II phosphorylation sites, similar to those of the human CD30, are also present. Two Mabs recognizing the extracellular domain of the murine CD30 have been generated (23). Both are capable of efficiently activating CD30 (23–25). The rat CD30 has also been cloned recently (26). The deduced rat CD30 protein consists of 493 aa with a relative high homology, particularly within the intracellular terminal C-terminus region, with the human and mouse proteins. Two mRNA transcripts, corresponding to those found in human CD301 cells of 3.4 and 2.3 kb, are transcribed in T-cells and in lung tissue, respectively. CD30 EXPRESSION IN NORMAL CELLS
CD30 is preferentially expressed by activated lymphoid cells. In normal peripheral lymphoid organs, CD301 cells are seen within the parafollicular areas and in the rim of the follicular centers. These interfollicular B and T cells have abundant cytoplasm and evident nucleoli, are proliferating (27), and often coexpress Bcl-6 (28). In addition, CD301 centroblasts are found within germinal centers (2). CD301 cells are also identified in the medulla of the thymus, frequently around the Hassal’s corpuscles, which express detectable CD30L (29). Despite readily evident mRNA transcription in the thymus (23, 24), surface CD30 expression on thymocytes is virtually undetectable. In contrast, using indirect immunofluorescence, a variable percentage (3–31%) of human peripheral blood lymphocytes have been demonstrated to express surface CD30. Many of these cells belong to the CD8 subset and produce IFN-g and IL-4 (30). In addition to B and T lymphocytes, lung macrophages (20), activated
NK cells (31), endothelial cells (32), and decidual cells (33) also express CD30 to variable extents. In vitro, CD30 expression on T cells can be achieved after mitogen activation, antigen receptor crosslinking, and as a result of viral infection (1, 23, 25, 34). Maximal expression is obtained within 3– 6 days, depending on the cell system used. Surface CD30L and CD30 expression have different kinetics and differ with respect to the T cell type in which they are preferentially expressed. After activation, CD30 is expressed by the majority of murine CD81 and a minority of CD41 cells. In contrast, CD30L is primarily expressed on non T cells and CD41 T cells and to a lesser extent on CD81 T cells (23). Activated human CD81, more frequently than CD41 cells, express high CD30 and belong exclusively to the CD45RO1 memory subset of T cells (34). The role of CD30 in these memory cells is unclear, particularly in consideration of the fact that in CD302/2 mice T cell memory responses appear normal (35). Activation via anti-CD3 alone generally induces weak CD30 expression. However, IL-2 enhances CD30 expression in human and murine T cells (25, 34). While endogeneous IL-4 allows and sustains (25, 36) its expression, CD30 is down-regulated by IFN-g (36). AntiCD28 causes upregulation of CD30 expression even in the absence of IL-4 (25, 37). In contrast, stimulation via CD30 results in the downregulation of CD28 (18). CD30 is preferentially and/or constitutively expressed by T cells producing Th2-type cytokines. Th0 and Th1 cells do not express CD30, or may only transiently express it after in vitro activation (38 – 41). However, CD30 expression is not an absolute and exclusive prerogative of Th2 clones. In fact, after in vitro activation by Ags that elicit either Th0, or Th1 and 2-type responses, CD301 T cell clones, producing IFN-g and/or other lymphokines, can be established (42). Finally, in mycobacterial infections, an elevated number of CD301 IFN-g producing T cells are found in affected lungs (43). It has been reported that in normal and in HIV-positive individuals the relatively large population of CD81CD301 T cells are able to produce not only IFN-g, but also IL-5 (44) and IL-4 (38). Interestingly, IFN-g production is controlled by IL-12 only in CD301 but not CD302 T cells (45). Overall, the findings indicate, however, that Th2 cells and IL-4 production are strongly linked with CD30 expression. Many investigators have demonstrated a correlation between the presence of CD301 T cells and of soluble CD30 with Th2-response-associated clinical entities (40). This is, perhaps, the case in the Omen syndrome. These children, who exhibit severe immunodeficiency, characterized by clinical and laboratory features reminiscent of Th2 responses, have numerous CD301 cells within their lymphoid tissues and in the peripheral blood (46). CD301 cells and/or high serum CD30 levels, particularly during the acute phase of the disease, are also
CD30 IN NORMAL AND NEOPLASTIC CELLS
found in patients with systemic lupus erythematosus (47), rheumatoid arthritis (48), Wegener’s granulomatosis (49), systemic sclerosis (50), and atopic dermatitis (51, 52). Lymphoid cells carrying viral EBV, HTLV-I (1), or Saimiri virus (53) genomes express high levels of CD30. Whether this expression is directly due to viral transactivation of CD30 and/or simply correlates with cell activation and proliferation is unclear. However, it should also be noted that, in vivo, a higher number of CD301 cells and/or high levels of circulating soluble CD30 are often detected after viral infection. In the case of acute infectious mononucleosis, CD301 B and T cells are often positive for EBV and display significant morphological atypia. Patients positive for hepatitis C (54), hepatitis B (55), or HIV (56) often have high serum CD30. High titers of CD30 have been correlated with the peak concentration of HIV Ag in acute primary HIV infection and the rate of viral replication (56, 57). In fact, soluble CD30 and TNF-a levels are useful parameters in predicting the clinical course of primary HIV infections (58). A contributing factor to enhanced viral production could be the activation of CD30 on CD41 T cells via CD30L on other cells, as it results in the activation of NF-kB binding to sites in the HIVLTR regions, thereby enhancing viral transcription (19, 59, 60). CD30 EXPRESSION IN NEOPLASTIC CELLS
Overexpression of CD30 has been documented not only in lymphoproliferative disorders, but also in rare solid tumors, including embryonal carcinomas (61, 62) and some seminomas (63). As in the case of CD301 lymphoproliferative disorders, receptor–ligand interaction may function in the autocrine growth regulation of embryonal carcinoma cells (64). However, CD30 expression has become crucial in characterization of human lymphoproliferative disorders not only to identify HD but also to recognize ALCL and CD301 nonHodgkin Lymphoma (NHL). In the case of classical (nodular sclerosis, mixed cellularity, and lymphocyte depletion) HD, the large majority of Reed–Sternberg (RS) cells are positive for CD30 (65). In contrast, in the lymphocyte predominant (LP) variant of HD the neoplastic cells are weak to moderately positive (66, 67). Extensive studies of the Ig gene products of RS cells have confirmed that these neoplastic cells often exhibit VDJ rearrangement as well as somatic mutation and, therefore, are of B-cell origin (68 –71). Their normal cellular counterpart is still controversial, but they most likely represent germinal center B cells, possibly caught in the process of receptor editing. This hypothesis is supported by the fact that in LP and in some classical HD, the RS cells express Bcl-6 (72), a protein that is highly expressed by germinal center cells and by
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cells which have passed through the germinal center (73, 74). In HD, serum levels of CD30 are elevated in the majority of untreated patients and correlate with clinical features, such as stage, symptoms, and tumor burden, being of prognostic significance (75–77). Similarly, in ALCL very high levels of serum CD30 can be observed (78). Finally, considering that in normal individuals the percentage of CD301 cells is quite small, the expression of CD30 in tumor cells may be used to specifically target chemotherapeutic agents against CD301 neoplastic cells. This approach has been successfully used in vitro (79) and in animal models (80). The molecular mechanisms regulating the expression of CD30, as well as the possible alterations in such pathways in RS cells, are still largely unclear. One possibility is that the expression of CD30 on RS cells may be related to the stage of differentiation of the corresponding normal cell from which they are derived. If RS cells represent the transformation of germinal center cells, it is important to consider that CD301 B centroblasts are present within normal germinal centers and that CD30 expression may be related to a particular stage of B cell differentiation (81). On the other hand, RS cells often carry viral EBV genomic sequences (82, 83). In approximately 50% of all HD, the RS cells are EBV positive and EBV infection has been demonstrated to induce CD30 gene transcription and protein expression (84). Although CD30 is not a specific RS cell marker, analysis of its expression has assumed an important role in the differential diagnosis of HD. Moreover, the systematic utilization of immunohistochemical techniques has permitted the identification of a previously unrecognized category of NHL, now designated ALCL, which is of T cell origin and CD301. Before the discovery of CD30, these lymphomas were not recognized as a distinct clinicopathologic entity and, instead, were variously considered to be different NHL or other nonlymphoid malignancies. Finally, ALCL should be distinguished from other CD301 NHL. Among the CD301 T cell lymphomas, which in general have a better prognosis compared to the CD301 B-NHL (85), those of the skin even exhibit spontaneous regression (86). FUNCTIONAL ROLE OF CD30 IN NORMAL AND NEOPLASTIC CELLS
The function of CD30 is largely unknown. Emerging information indicates that the activation of CD30 may provide positive or negative signals. These pleiotropic effects of CD30 have been primarily elucidated in vitro. It was found that CD30 activation may result in enhanced cell proliferation, cell growth arrest, or apoptosis (15, 87). CD30 activation has been reported to increase the proliferation of “T-cell-like,” but not “B-cell-like” CD301 HD cell lines (15). The precise
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mechanisms regulating these processes are unclear. However, crosslinking of CD30 expressed by HDderived cell lines results in enhanced IL-6, TNF, and lymphotoxin (LT)-a release (37, 88), all cytokines which can trigger TNF-R1 (p75) and IL6-R expressed by RS cells and modulate their growth (89). Crosslinking of CD30 and CD40 results in the enhanced expression and secretion of ICAM-1 (CD54) and B7-1 (CD80) (37, 90). Many cell lines derived from mature B cells do not change their growth patterns nor are blocked after CD30 activation (15). On the other hand, crosslinking of CD30 on EBV-infected B cells, but not on Burkitt’s cell lines, enhances their Ig secretion. Finally, in Tlymphoblastoid cells and ALCL lines, CD30 crosslinking results in a block of proliferation or in cell death (15, 22). Using a chimeric CD8/CD30 molecule, Lee et al. have demonstrated that apoptosis of T cell hybridomas requires the multimerization of CD30 cytoplasmic domains and concomitant signal(s) via TCR (87). Signal transductions in Jurkat cells via CD30 also requires the presence of the TCR/CD3 complex (34). These findings indicate that CD30 acts as a coreceptor, possibly modulating the effect of the antigen receptor complex. More recently, the cloning of the CD30 and CD30L genes has opened new investigational avenues such as the generation of CD30 transgenic (Tg) (24) and knockout (2/2) mice (35). Using our CD30 Tg mice, in which expression of CD30 was directed to the T cells by use of the CD4 promoter, we demonstrated that concomitant engagement of CD3 and CD30 on thymocytes results in enhanced cell death, compared to that achieved by anti-CD3 alone (24). Moreover, we found that crosslinking of overexpressed CD30 alone enhanced spontaneous apoptosis. CD30 overexpression also enhances the deletion of Vb81CD41CD82 thymocytes by low doses of SEB and of CD41CD81 DO11.10 Tg thymocytes expressing low-intermediate antiovalbumin TCR by specific peptides (24). These findings support the hypothesis that CD30 may be involved in negative selection in the thymus. This is in agreement with data derived from CD302/2 mice (35). These animals have large thymi and normal lymphoid peripheral organs and show an impaired negative selection in vitro and in vivo as demonstrated in a/b or g/d TCR-transgenic animals. However, none of these animal models have thrown much light on the role of CD30 in mature peripheral T cells. Purified CD301 Tg T cells crosslinked with anti-CD30 Mabs are activated and enter cell cycle replication. Furthermore, synergistic stimulation occurs between submitogenic anti-CD3 concentrations and anti-CD30 (24). Similar results were obtained with BALB/cJ cells in which CD30 expression was induced by anti-CD3 and anti-CD28 in the presence of IL-4 (25). Thus, CD30 can act as a costimula-
tory molecule in synergism with the CD3/TCR complex. MEDIATION OF CD30 SIGNALING
The CD30 engagement by its corresponding ligand and/or by functional anti-CD30 Mab induces a rapid series of changes largely mediated by the interactions of its cytoplasmic portion with multiple transducer proteins (Fig. 1). Four TRAF molecules, 1, 2, 3, and 5, can bind independently and/or as a complex to the cytoplasmic tail of CD30. TRAF1 and 2, 3, and 5 bind to short peptide sequences located at 462– 466, 480 – 485, and 464 – 470, respectively (8 –10). Recently a new region defined as the D1 domain has also been shown to be involved in a pathway that leads to activation of NF-kB (11). In in vitro systems, the activation of CD30 has been associated with NF-kB activation through TRAF2-dependent and independent pathways (11, 17). These findings are indirectly supported by studies on Tg mice overexpressing a dominant negative form of TRAF2 (91) or on TRAF22/2 (92) mice, demonstrating that, in absence of functional TRAF2, NF-kB activation can still be achieved by TNF-R1 activation, even though c-jun activation is impaired. It should be noted, however, that CD30 crosslinking on thymocytes from our CD30 Tg mice does not appear to lead to any activation of NF-kB or c-jun pathways (24). However, using the CD30 Tg mice, we could demonstrate that the apoptotic pathway in Tg thymocytes is mediated by caspases 1 and 3, since it was blocked by specific peptides. Moreover, Bcl-2 plays an important role, considering that in double transgenic mice for CD30 and Bcl-2, the CD30-induced apoptosis was completely inhibited (24). With respect to the pleiotropic effects of anti-CD30, additional factors should be considered, as different CD30-mediated responses could depend on the concomitant expression of other molecules. The differential expression of proteins such as Nur77 (93), TRIP, and TRAF1 (94) in different cells and/or at different stages of cell differentiation, may control and modulate different mediators and/or pathways, thereby influencing the overall results obtained with agents inducing apoptosis under some, but not all, circumstances. Finally, the concomitant engagement of CD30 and other molecules, including TNF-R, can result in the modulation of shared transduction molecules which may result in the modulation or inhibition of specific pathways. CD30 activation results in an enhanced degradation of TRAF2 (96), thus the effects resulting from the coactivation of molecules acting via TRAF2 may be abolished or preferentially shifted toward alternative pathways (91, 95). Germinal center and/or activated B cells, when engaged with anti-CD40, undergo Ig class switch and exhibit downregulation of CD30 expression. How-
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also express CD30L (101). These findings suggest that CD30 and CD30L, contrary to other members of the TNF superfamily, can elicit multidirectional signals leading to the activation of the interacting cellular elements. REFERENCES
FIG. 1. CD30 and signal transduction pathway. The crosslinking of CD30 may result in the activation of different pathways. In thymocytes CD30 crosslinking leads to the activation of caspase 1 and 3 and apoptosis. This pathway may be blocked by cIAP and is bcl-2 dependent. In the case of mature T cells, CD30-CD30L complexes result in the engagement of TRAF molecules which mediate the activation of NF-kB. TRIP inhibits the TRAF-mediated cell activation/growth, promoting indirectly proapoptotic signals.
ever, if CD40 and CD30 are simultaneously engaged CD40-induced germline transcription of the e gene is consistently inhibited (81) and switching is effectively hampered (96). It was originally speculated that CD30, as other members of the TNF-R superfamily, would be the only partner of the receptor–ligand pair, capable of activating a downstream cascade. Recently, it has been suggested that, in the case of CD30/CD30L complexes, this model may be too simplified. In fact, when CD30L is engaged by soluble CD30-Ig it can, in the presence of IL-2, IL-4, or IL-5, induce mouse B cell differentiation and Ig production (97). In addition, the activation of CD30L can elicit the production of IL-8 and a rapid oxidative burst by freshly isolated neutrophils. Finally, anti-CD30L Mab can induce IL-6 production in CD30L1 T lymphocytes (98). These findings are interesting in view of the complex cellular interactions and cytokine-mediated effects in HD (99). In classical HD, neutrophils and eosinophils are characteristically present, representing an important and often specific component of this lesion. It is of interest that in HD, these cells express high levels of surface CD30L and that IL-5, IL-3, and GM-CSF, which can all be produced by RS cells (14), are able to enhance CD30L expression on purified eosinophils from normal subjects (100). In addition, T cells within the HD lesion
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Received September 9, 1998; accepted October 1, 1998
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