Measles Virus Contact with T Cells Impedes Cytoskeletal Remodeling Associated with Spreading, Polarization, and CD3 Clustering (original) (raw)
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Measles virus interacts with human SLAM receptor on dendritic cells to cause immunosuppression
Virology, 2004
Measles virus (MV) infects dendritic cells (DCs) resulting in immunosuppression. Human DCs express two MV receptors: CD46 and human signaling lymphocyte activation molecule (hSLAM); thus, the role played by either alone is unclear. Because wild-type (wt) MV uses hSLAM receptor preferentially, we dissected the molecular basis of MV-DC interaction and resultant immunosuppression through the hSLAM receptor by creating transgenic (tg) mice expressing hSLAM on DCs. After infection with wt MV, murine splenic DCs expressing hSLAM receptor had less B7-1, B7-2, CD40, MHC class I, and MHC class II molecules on their surfaces and displayed an increased rate of apoptosis when compared to uninfected DCs. Further, MV-infected DCs failed to stimulate allogeneic T cells and inhibited mitogendependent T-cell proliferation. Individual expression of human SLAM, interferon a/h receptor, tumor necrosis factor-a, and lymphotoxin-a or h from T cells was not required for MV-infected DCs to inhibit the proliferation of T cells.
Measles virus: cellular receptors, tropism and pathogenesis
Journal of General Virology, 2006
Measles virus (MV), a member of the genus Morbillivirus in the family Paramyxoviridae, is an enveloped virus with a non-segmented, negative-strand RNA genome. It has two envelope glycoproteins, the haemagglutinin (H) and fusion proteins, which are responsible for attachment and membrane fusion, respectively. Human signalling lymphocyte activation molecule (SLAM; also called CD150), a membrane glycoprotein of the immunoglobulin superfamily, acts as a cellular receptor for MV. SLAM is expressed on immature thymocytes, activated lymphocytes, macrophages and dendritic cells and regulates production of interleukin (IL)-4 and IL-13 by CD4 + T cells, as well as production of IL-12, tumour necrosis factor alpha and nitric oxide by macrophages. The distribution of SLAM is in accord with the lymphotropism and immunosuppressive nature of MV. Canine distemper virus and Rinderpest virus, other members of the genus Morbillivirus, also use canine and bovine SLAM as receptors, respectively. Laboratory-adapted MV strains may use the ubiquitously expressed CD46, a complement-regulatory molecule, as an alternative receptor through amino acid substitutions in the H protein. Furthermore, MV can infect SLAM " cells, albeit inefficiently, via the SLAM-and CD46-independent pathway, which may account for MV infection of epithelial, endothelial and neuronal cells in vivo. MV infection, however, is not determined entirely by the H protein-receptor interaction, and other MV proteins can also contribute to its efficient growth by facilitating virus replication at post-entry steps. Identification of SLAM as the principal receptor for MV has provided us with an important clue for better understanding of MV tropism and pathogenesis.
Immunological Reviews, 2002
Summary: The reorganization of membrane, cytoskeletal and signaling molecules during immune interactions is critical for the generation of immune response. At the initiation of the T cell-antigen presenting cell (APC) interaction, antigen-independent weak adhesion forces allow the scanning of the APC surface by the T cell receptor for specific antigens. The stabilization of T cell-APC conjugates involves the segregation of membrane and intracellular signaling proteins, driven by reorganization of membrane microdomains and cytoskeletal changes. In early T cell-APC cognate interactions, the microtubular cytoskeleton undergoes drastic changes that lead to microtubule-organizing center (MTOC) reorientation to the vicinity of the cell-cell contact area. Recent data on the dynamics of MTOC redistribution and its influence in T cell-APC conjugate stabilization, together with the description of an increasing number of signaling molecules associated to this complex, underscore the key role of MTOC translocation in the T cell response. We focus on the mechanisms that control the early MTOC reorientation during T cell-APC interaction and the relevance of this process to T cell activation.
Measles Virus Glycoprotein Complex Assembly, Receptor Attachment, and Cell Entry
Current Topics in Microbiology and Immunology
Measles virus (MV) enters cells by membrane fusion at the cell surface at neutral pH. Two glycoproteins mediate this process: the hemagglutinin (H) and fusion (F) proteins. The H-protein binds to receptors, while the F-protein mediates fusion of the viral and cellular membranes. H naturally interacts with at least three different receptors. The wild-type virus primarily uses the signaling lymphocyte activation molecule (SLAM, CD150) expressed on certain lymphatic cells, while the vaccine strain has gained the ability to also use the ubiquitous membrane cofactor protein (MCP, CD46), a regulator of complement activation. Additionally, MV infects polarized epithelial cells through an unidentified receptor (EpR). The footprints of the three receptors on H have been characterized, and the focus of research is shifting to the characterization of receptor-specific conformational changes that occur in the H-protein dimer and how these are transmitted to the F-protein trimer. It was also shown that MV attachment and cell entry can be readily targeted to designated receptors by adding specificity determinants to the H-protein.
Journal of Experimental Medicine, 1997
Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. Dendritic cells (DC) are professional antigen-presenting cells required for initiation of primary immune responses. To determine whether infection of DC by measles virus (MV) may play a role in virus-induced suppression of cell-mediated immunity, we examined the ability of CD1a ϩ DC derived from cord blood CD34 ϩ progenitors and Langerhans cells isolated from human epidermis to support MV replication.
Mechanism of Measles Virus–Induced Suppression of Inflammatory Immune Responses
Immunity, 2001
small animal model has impeded progress in understanding the mechanisms of MV-induced immune ab-Bruce Loveland, † Jean-Franç ois Nicolas,* Chantal Rabourdin-Combe,* and Branka Horvat* ‡ § normalities. Monkeys have been used (Auwaerter et al., 1999), but their utilization is extremely restricted by lim-* INSERM U503, CERVI Immunobiologie Fondamentale et Clinique ited supply and high cost. SCID mice grafted with human PBL showed a reduced production of human IgG after Lyon, 69365 France MV infection (Tishon et al., 1996); nevertheless, this model is not convenient for an accurate analysis of anti-† The Austin Research Institute Heidelberg, VIC 3084 gen-specific responses due to the lack of MHC compatibility between murine stromal tissue and human PBL. Australia Cotton rats, susceptible to MV infection, subsequently develop immunosuppression (Niewiesk et al., 1997) but compared to mice are genetically and immunologically Summary poorly characterized. Recently, MV infection of mice expressing CD46, human cellular receptor of MV, was Measles virus (MV) causes profound immunosuppresreported to be associated with immunosuppression sion, resulting in high infant mortality. The mechanisms (Oldstone et al., 1999), though several other reports sugare poorly understood, largely due to the lack of a gested that MV proteins alone can inhibit in vitro immune suitable animal model. Here, we report that particular response (Karp et al., 1996; Schlender et al., 1996; Rava-MV proteins, in the absence of MV replication, could nel et al., 1997). Although these studies confirmed the generate a systemic immunosuppression in mice existence of MV-induced restraint of immune response, through two pathways: (1) via MV-nucleoprotein and the importance of MV replication and the mechanism its receptor Fc␥R on dendritic cells; and (2) via virus responsible for induction of immunosuppression in vivo envelope glycoproteins and the MV-hemagglutinin remains elusive. cellular receptor, CD46. The effects comprise reduced In this report, we investigated the roles of MV proteins hypersensitivity responses associated with impaired in the generation of immunosuppression in vivo. Two function of dendritic cells, decreased production of ILtypes of T cell-dependent inflammatory reactions were 12, and the loss of antigen-specific T cell proliferation. analyzed: delayed type hypersensitivity (DTH) to keyhole These results introduce a novel model for testing the limpet hemocyanin (KLH) mediated by CD4 ϩ T cells immunosuppressive potential of anti-measles vac-(Grabbe and Schwarz, 1998), and contact hypersensitivcines and reveal a specific mechanism of MV-induced ity (CHS) induced by epicutaneous exposure to the hapmodulation of inflammatory reactions. ten dinitrofluorobenzene (DNFB) and mediated by CD8 ϩ T cells (Bour et al., 1995; Kehren et al., 1999). Dendritic Introduction cells play the critical role in the initiation of these inflammatory responses (Grabbe and Schwarz, 1998). We Measles virus (MV) is responsible for an acute childhood demonstrated that MV replication is not necessary for disease that each year infects over 40 million individuals the induction of immunosuppression and that inactiand causes the death of more than 1 million, primarily in vated MV efficiently suppresses hypersensitivity rethe developing world (Murray and Lopez, 1997). The high sponses in mice, after the interaction of viral envelope mortality is associated with transitional MV-induced proteins and nucleoprotein with their respective cellular immunosuppression, enabling secondary infections that receptors. These results suggest that a conventional severely complicate the course of the disease (Beckford murine hypersensitivity model could be directly applicaet al., 1985; Griffin et al., 1994). Measles infection is ble in testing the immunosuppressive effects of antifollowed by the ablation of delayed-type hypersensitivity measles vaccines. Furthermore, they provide evidence responses to tuberculin (Von Pirquet, 1908; Tamashiro et that MV proteins directly induce suppression of inflamal., 1987) and impaired in vitro proliferation of peripheral matory reactions and impair dendritic cell function and blood lymphocytes (PBL) (Hirsch et al., 1984) as well as have important implications in understanding the pathoallospecific cytolytic activity (Galama et al., 1980). Many genesis of MV-induced inhibition of immunity. immunological alterations observed during measles infection also occur at lesser magnitude after vaccination Results of children using attenuated MV (Fireman et al., 1969; Hussey et al., 1996). Inactivated Measles Virus Inhibits Hypersensitivity Responses in Mice ‡ To whom correspondence should be addressed (e-mail: horvat@ We first analyzed whether MV particles could affect the cervi-lyon.inserm.fr).
Disruption of Akt kinase activation is important for immunosuppression induced by measles virus
2001
Suppression of immune functions is the major cause of infant death associated with acute measles. Because the frequency of MV-infected peripheral blood cells is low throughout infection, indirect mechanisms such as surface-contact-mediated signaling are likely to account for the proliferative unresponsiveness of lymphocytes to polyclonal and antigen-specific stimulation seen ex vivo 1-3. We have shown that expression of the MV fusion (F) and hemagglutinin (H) glycoproteins is necessary and sufficient to induce proliferative unresponsiveness in uninfected human and rodent lymphocytes in vitro and in vivo 4-6. We demonstrated this using infected cells, cells transfected to express these proteins and ultraviolet-light-inactivated MV (UV-MV). The inhibitory activity of the MV F/H complex depends on proteolytic activation of the F protein, but not on cellular fusion or the generation of soluble mediators, indicating that inhibition is mediated by a surface-contact signal 7,8. In vitro and in vivo, MV F/H signaling causes cell-cycle retardation with accumulation of cells in the G 0 /G 1-phase 9,10. This is linked to a reduced expression and activity of G 1 cyclin-dependent kinase (CDK) complexes, and delayed degradation of p27 Kip (ref. 6). The importance of interleukin (IL)-2 for T-cell survival, functional differentiation and S-phase progression is well established 11. Heterodimerization of the IL-2R β and γ subunits allows activation of src-family tyrosine kinases and Janus kinases, JAK1 and JAK3, thus creating binding sites for signaling molecules such as signal transducer and activator of transcription (STAT)-3, STAT5 and Shc (refs. 12-14). In T cells, IL-2-dependent activation of the phosphatidylinositol-3 kinase (PI3K) is sufficient to activate human protein kinase B/Akt (ref. 15), and both antiapoptotic and proliferative signals are transduced by this pathway 16,17. Akt was also implicated as a positive regulator of NF-κB activation in Jurkat T cells 18. Importantly, IL-2R-dependent PI3K and subsequent Akt activation is coupled to the cell-cycle machinery in T cells 19. To investigate MV F/H-induced signaling, we focused on IL-2R signaling because proliferation of immunosuppressed T cells was not restored by exogenous IL-2 treatment in vitro and ex vivo 9,10 , although mitogen-induced upregulation of the IL-2R was unaffected and IL-2 synthesis was marginally reduced. We show here that MV in vitro and in vivo efficiently interfered with the IL-2-dependent activation of Akt kinase pathway in T cells, but not of the JAK/STAT pathway. MV induces IL-2 unresponsiveness in vitro MV F/H proteins inhibit mitogen-induced proliferation of peripheral blood T cells in vitro and in vivo 4-10. Treatment of human primary peripheral blood lymphocytes (PBLs) with UV-MV, but not with equivalent amounts of mock supernatant, caused a dose-dependent inhibition of PHA-induced proliferation º(Fig. 1a, inset). As seen with UV-inactivated MV-infected cells 9 , upregulation of the IL-2R chains was largely unaffected by UV-MV treatment at both the RNA (Fig. 1b) and protein levels (Fig. 1c), and the synthesis of IL-2 was only slightly reduced in the presence of UV-MV (data not shown). As with UV-inactivated effector cells 9,10 , UV-MV prevented the mitogen-induced proliferation of uninfected PBL and this could not be restored by exogenous IL-2 (Fig. 1a). Thus, the signal imposed on T cells by surface contact with UV-MV led to a disruption of IL-2R signaling in vitro. This finding was supported by experiments with Kit-225 cells, which are dependent on IL-2 for mitosis but not for survival (Fig. 1d). When added to Kit-225 cells, UV-MV, but not UV-VSV (vesicular stomatitus virus, which is non-immunosuppressive in our system 4) or mock supernatant, caused a dose-dependent inhibition of IL-2-stimulated proliferation of these cells (Fig. 1e). MV-mediated signaling does not interfere with JAK/STAT IL-2 signaling in T cells involves JAK1/JAK3-dependent activation of STAT3 and STAT5. We immunoprecipitated JAK1 and JAK3 from extracts of primary human T cells treated with mock supernatant or with UV-MV, and analyzed them for their autophosphorylation activity in vitro (Fig. 2a). We detected no in
Journal of virology, 1999
CD46, which serves as a receptor for measles virus (MV; strain Edmonston), is rapidly downregulated from the cell surface after contact with viral particles or infected cells. We show here that the same two CD46 complement control protein (CCP) domains responsible for primary MV attachment mediate its downregulation. Optimal downregulation efficiency was obtained with CD46 recombinants containing CCP domains 1 and 2, whereas CCP 1, alone and duplicated, induced a slight downregulation. Using persistently infected monocytic/promyelocytic U937 cells which release very small amounts of infectious virus, and uninfected HeLa cells as contact partners, we then showed that during contact the formation of CD46-containing patches and caps precedes CD46 internalization. Nevertheless, neither substances inhibiting capping nor the fusion-inhibiting peptide Z-D-Phe-L-Phe-Gly-OH (FIP) blocked CD46 downregulation. Thus, CD46 downregulation can be uncoupled from fusion and subsequent virus uptake. ...