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Silencing T cells or T-cell silencing: concepts in virus-induced immunosuppression

¹ Institute for Virology, University of Würzburg, Versbacher Straße 7, D-97078 Würzburg, Germany
² Institut für Virologie des Universitätsklinikums Essen, D-45122 Essen, Germany

Correspondence
Sibylle Schneider-Schaulies
s-s-s{at}vim.uni-wuerzburg.de

	ABSTRACT

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The ability to evade or suppress the host's immune response is a property of many viruses, indicating that this provides an advantage for the pathogen to spread efficiently or even to establish a persistent infection. The type and complexity of its genome and cell tropism but also its preferred type of host interaction are important parameters which define the strategy of a given virus to modulate the immune system in an optimal manner. Because they take a central position in any antiviral defence, the activation and function of T cells are the predominant target of many viral immunosuppressive regimens. In this review, two different strategies whereby this could be achieved are summarized. Retroviruses can infect professional antigen-presenting cells and impair their maturation and functional properties. This coincides with differentiation and expansion of silencing T cells referred to as regulatory T cells with suppressive activity, mainly to CD8⁺ effector T cells. The second concept, outlined for measles virus, is a direct, contact-mediated silencing of T cells which acquire a transient paralytic state.

Published online ahead of print on 3 March 2006 as DOI 10.1099/vir.0.81713-0.

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The interaction of viruses with their hosts is a dynamic, adaptive process characterized by the struggle of the latter to control and combat the infection by immune responses and in which the invading pathogen tries either to counteract or evade in order to survive and spread. Both arms of the immune system, the innate and adaptive immune systems, play important roles in protecting vertebrates against viral infections. Barriers imposed by the innate immunity, e.g. type I interferons or natural killer cells, are highly efficient, and this is reflected by the fact that proteins aiming to circumvent these immune responses can be found in many viruses. However, this review will focus on the escape mechanisms of viruses from adaptive T-cell responses. Escaping control by the adaptive immunity can be achieved by various mechanisms including competing aggressively against immune control by fast replication/dissemination or generation of antigenic variants. A more sophisticated way of immune evasion is exerted efficiently by members of the Herpesviridae, which encode a plethora of proteins in their genomes which prevent antigen presentation. From the virus point of view, these evasion strategies provide a selective advantage. In contrast, viruses can also cause a generalized immunosuppression which may be required to facilitate their own spread, but will also be of advantage for opportunistic pathogens. The magnitude, targets and effector mechanisms for immunosuppression as well as its pathogenic significance certainly may differ between viruses. In the last few years, advances have been made in understanding the mechanisms of virus-induced immunosuppression. It has become obvious that there is not a single way in which viruses mediate general immunosuppression, since different mechanisms have been defined in different virus infections. In particular, more direct mechanisms of immunosuppression in which viral proteins suppress functions of immune cells have been described, as well as more indirect mechanisms in which viruses induce inhibitory cells or mediators of the immune system, which in turn suppress lymphocytes with antiviral activity. This review compares direct versus indirect mechanisms of virus-induced immunosuppression by focusing on well-characterized infections with measles virus (MV) and various retroviruses. In patients infected with retroviruses or MV, immunosuppression plays a central role in virus-induced pathology and we discuss the mechanisms that are involved. Here, MV is described as an example of viruses that inhibit T-cell activation, proliferation or viability directly by means of viral proteins. In contrast, retroviruses have recently been reported to suppress T-cell responses indirectly by inducing regulatory T cells which then act to prevent activation of effector T or B cells. Both mechanisms of virus-induced immunosuppression have to be studied in detail in order to develop new therapeutic approaches to overcome immune failure.

Retroviruses: the silencing T-cell concept
One hallmark of many retroviral infections is a severe virus-induced immunosuppression. For example, human immunodeficiency virus- (HIV-) infected patients not only develop transient immunosuppression but progress to a severe immunodeficiency during chronic infection. Many different features of this viral infection seem to contribute to the breakdown of the immune system. Firstly, HIV infects CD4-positive helper T (Th) cells and antigen-presenting cells [APCs; macrophages and dendritic cells (DC)] and induces dysfunction and cell death in these populations. Progression to AIDS is negatively correlated with CD4⁺ T-cell numbers, indicating that the loss of Th cells is a critical step in the development of HIV-induced immunodeficiency. It is still a matter of debate whether the decrease in CD4⁺ T-cell numbers is induced solely by direct viral infection of these cells or whether indirect effects also play a role. There is evidence that apoptosis of uninfected bystander T cells and impaired thymic output of T cells might also contribute to the loss of CD4⁺ T cells (Gougeon, 2003). In addition to mechanisms leading to Th cell disappearance and immunodeficiency, HIV can also interfere with antigen presentation to T cells. For example nef, an accessory gene of HIV, has been reported to downregulate class I major histocompatibility complex (MHC) molecules efficiently on infected cells (Johnson & Desrosiers, 2002). As a consequence, these cells can no longer be recognized and killed by cytotoxic T lymphocytes (CTL). Furthermore, several studies have shown that mutations in T-cell epitopes occur frequently during HIV infection, leading to viral escape from T-cell activity (Goulder & Watkins, 2004). Virus-induced changes in the cytokine production of T cells have also been reported in HIV infection. From these studies it has been postulated that a Th1 to Th2 switch might contribute to HIV pathogenesis (Clerici & Shearer, 1993).

The overall relevance of the different mechanisms of HIV-induced immunosuppression and immunodeficiency mentioned above for disease progression and AIDS has not been completely understood. Several reviews have recently been published which describe and discuss these aspects of HIV immunopathogenesis in great detail (Johnson & Desrosiers, 2002; Gougeon, 2003; Goulder & Watkins, 2004). We have therefore focused on a newly described mechanism of retrovirus-mediated immunosuppression involving regulatory T cells. This indirect mechanism of viral immune evasion has been discovered in the Friend retrovirus (FV) mouse model (Iwashiro et al., 2001), yet there is strong evidence that it might also play an important role in chronic viral infections in humans, including HIV infection.

Regulatory T cells in HIV infection
In addition to the direct immunosuppressive effects of HIV and its proteins, it has been reported that indirect mechanisms can also contribute to retrovirus-induced immunosuppression. One hallmark of many retroviral infections is the development of a functional impairment of T cells which are not directly infected by a virus. The features of this T-cell dysfunction and the possible role of regulatory T (Treg) cells in this immunosuppression will be the focus of the first part of this review.

Treg cells are T cells that suppress other T-cell responses (for review see Wickelgren, 2004). Several subsets of Treg cells which can be distinguished by their phenotype and function have been identified. These include natural Treg cells, which are a subset of T cells expressing the high-affinity interleukin-2 (IL-2) receptor alpha chain (CD25). These cells are known to play a central role in the maintenance of immunological homeostasis and self-tolerance in autoimmunity. In addition, pathogen-specific Treg cells are known to expand during infections and to be involved in preventing infection-induced immunopathology (Fig. 1). These cells are referred to as induced Treg cells. Induced Treg cells are able to destroy or functionally impair effector T cells at a time point of infection when most of the pathogen has successfully been eliminated (Fig. 1). However, recent data indicate that induced Treg cells can be involved in T-cell dysfunction and impaired pathogen clearance in chronic infections. For example, functional impairment of effector CD4⁺ T-cell and CD8⁺ T-cell responses has been described for patients infected with HIV (Trimble & Lieberman, 1998; Appay et al., 2000; Lieberman et al., 2001; Migueles et al., 2002; Hess et al., 2004). Since HIV is genetically highly variable, escape from T-cell responses by mutations in T-cell epitopes has been put forward as a major reason for the loss of T-cell activity in chronically infected carriers (O'Connor et al., 2001; Peyerl et al., 2004). However, evidence suggests that at least some viral epitopes of HIV are recognized by T cells throughout the chronic phase of infection (Draenert et al., 2004). In addition, levels of virus replication in infected patients were associated in most studies with functional properties of T cells rather than with escape mutations of the virus (Rosenberg et al., 1997; Migueles et al., 2002; Draenert et al., 2004; Hess et al., 2004; Koibuchi et al., 2005). T-cell dysfunctions that have been described in HIV-infected patients or other retroviral infections of animals include impaired antigen-specific T-cell proliferation (Dittmer et al., 1994; Rosenberg et al., 1997, 1999; Lichterfeld et al., 2004), altered cytokine production by CD4⁺ T cells (Clerici & Shearer, 1993), suppressed interferon (IFN) production by T cells (Dittmer et al., 2004) and reduced production of cytotoxic molecules by CD8⁺ T cells (Appay et al., 2000; Migueles et al., 2002; Zelinskyy et al., 2005). However, the mechanisms underlying these features of retrovirus-induced immunosuppression have remained elusive in most of these studies.

View larger version (21K): [in this window] [in a new window]   Fig. 1. How induced Treg cells function during a virus infection. When a viral infection occurs, the CD8+ CTLs become highly activated and start to proliferate. These cells kill virus-infected cells and thus fight the virus itself. However, once most of the virus has been eliminated, the CTLs have to be suppressed otherwise there is the danger that they may start to attack uninfected cells of the body, thus causing autoimmune disease. This suppression of the CTLs is carried out by CD4+ Treg cells. The latter also start to proliferate during the infection, although there is a time delay so that they are only able to start switching off the CTLs once the defence against the virus has been successfully completed. Viruses might disturb this balance between the CTLs and Treg cells by infecting DC and thus interfere with DC maturation and cytokine production. There is experimental evidence that immature DC stimulate Treg cells rather than Th cells, which could result in severe suppression of CTL responses and the development of chronic infections.

Retrovirus-induced regulatory T cells mediate immunosuppression in mouse models
The Friend retrovirus mouse model.
Using the FV model, it has recently been demonstrated that Treg cells induce immunosuppression and contribute to a form of retrovirus evasion from CTL elimination (Dittmer et al., 2004). Pathogenic FV is a complex of two retroviruses, the Friend murine leukaemia helper virus (F-MuLV) and the spleen focus-forming virus (SFFV). Co-infection of cells by the two viruses allows SFFV to spread by being packaged into F-MuLV-encoded virus particles. FV infection of susceptible adult mice induces polyclonal proliferation of erythroid precursor cells, causing severe splenomegaly. This proliferation is caused by the binding of the SFFV gp55 envelope glycoproteins to the erythropoietin receptors of nucleated erythroid cells (Hoatlin & Kabat, 1995). In susceptible mice, which fail to mount protective immune responses, infection leads to fully malignant erythroleukaemias (Hasenkrug & Chesebro, 1997). In addition to erythroleukaemia, FV induces the suppression of antibody and T-cell responses during acute infection (Ceglowski & Friedman, 1968; Morrison et al., 1987). It was previously demonstrated that the severity of FV-induced splenomegaly and immunosuppression was strongly influenced by the H-2D class I gene region of the MHC (Hasenkrug & Chesebro, 1997). Infection of susceptible strains (H-2D^d) leads to lethal leukaemia, whereas although resistant strains of mice (H-2D^b) may be able to control acute infection, they are nevertheless not able to eliminate the virus completely and thus a chronic infection ensues (also referred to as persistent infection in this review). Recent studies indicate that the inability of cytotoxic T cells to eradicate persistent FV infection is related to effector dysfunction in virus-specific CD8⁺ T cells (Dittmer et al., 2004).

CD8⁺ T-cell dysfunction in chronic FV infection.
CD8⁺ dysfunction in chronic FV infection has been proven by the failure of adoptively transferred FV-specific CD8⁺ T cells [from T-cell-receptor (TCR) transgenic mice] to reduce viral loads, despite the activation and proliferation of the CD8⁺ T cells in persistently infected mice. Thus, transferred CD8⁺ T cells recognize their cognate antigen in persistently infected mice but do not respond to it effectively. The functional impairment of those CD8⁺ T cells not infected by the virus directly involves the severely reduced production of IFN- and the cytotoxic molecules perforin, granzyme A and granzyme B (Dittmer et al., 2004; Zelinskyy et al., 2005). Interestingly, downregulation of the production of these molecules by CD8⁺ T cells seems to be at the translational rather than the transcriptional level. Consequently, CD8⁺ T cells from chronically infected mice are unable to degranulate and kill FV-labelled target cells in vivo (Zelinskyy et al., 2005).

Induced Treg cells in FV infection.
Evidence from CD4/CD8 T-cell co-transfer experiments implicates CD4⁺ Treg cells in suppressing the ability of CD8⁺ T cells to produce IFN-. The downregulation of IFN- expression by CD8⁺ T cells correlates with IL-10 production by the co-transferred CD4⁺ T cells from persistently infected mice. The production of the immunosuppressive cytokine IL-10 by CD4⁺ T cells might be involved in functional impairment of CD8⁺ T cells, since IL-10 is associated with reduced IFN- production and immunosuppression in acute FV infection (Dittmer et al., 2002). However, other mechanisms of Treg-cell-mediated suppression have been described, such as CTL-associated antigen 4, TGF- or the as-yet undefined molecules that require cell-to-cell contact which might also play a role in virus-induced immunosuppression (Mills, 2004). Surface markers of Treg cells have recently been analysed in the FV model. CD25 is a widely used marker for natural Treg cells (Sakaguchi, 2003). However, it was shown previously that a population of CD25⁺ CD4⁺ T cells acquires suppressive activity in chronic FV infection which is not present in cells from naive mice (Dittmer et al., 2004). The experiments demonstrated that CD25⁺ CD4⁺ T cells expand during acute FV infection, but no expansion of this population has been detected during chronic infection as yet (G. Zelinskyy and U. Dittmer, unpublished data). Thus, it might be a qualitative rather than a quantitative difference in the CD25⁺ CD4⁺ population that leads to the appearance of CD25⁺ Treg cells during FV infection. Other than the CD4⁺ CD25⁺ Treg cells, a CD4⁺ CD25^– population with suppressive activity was found during chronic FV infection (Dittmer et al., 2004). Glucocorticoid-induced tumour necrosis factor receptor (GITR), which has been associated with Treg-cell functions (Shimizu et al., 2002), is a co-stimulatory molecule and seems to be a functional marker of FV-induced Treg cells (G. Zelinskyy and U. Dittmer, unpublished data). The CD4⁺ GITR⁺ subset increases in numbers at around 2 weeks post-infection, the same phase of infection when CD8⁺ T cells lose their function. Thus, this CD4⁺ T-cell population is associated with suppressive activity during acute FV infection. In addition, it has been reported that the treatment of FV- or LP-BM5 retrovirus- (which induces murine AIDS) infected mice with an antibody against GITR can overcome CD8⁺ T-cell dysfunction and retrovirus-induced immunosuppression (Beilharz et al., 2004; Dittmer et al., 2004; He et al., 2004). The findings indicate that GITR, which has been suggested to block the suppressive function of Treg cells or to make CD8⁺ T cells refractory to Treg-cell suppression (Shimizu et al., 2002; Stephens et al., 2004), might be a functionally important molecule for induced Treg cells in chronic retroviral infection. Another surface marker that seems to be expressed on retrovirus-induced Treg cells is the E 7 integrin CD103, an epithelial cadherin-specific integrin involved in the homing and retention of T cells (Ericsson et al., 2004). Similar to CD4⁺ GITR⁺ T cells, a clear correlation was found between the expansion of CD4⁺ CD103⁺ T cells and the development of CD8⁺ dysfunction during acute FV infection (G. Zelinskyy and U. Dittmer, submitted). Recently, it has been published that CD103 controls the retention of Treg cells at a site of Leishmania major infection (Suffia et al., 2005). However, it is not clear why splenic Treg cells from mice persistently infected with FV express CD103, since the spleen does not normally contain epithelial cells. During chronic FV infection, more the 70 % of the CD4⁺ GITR⁺ or CD4⁺ CD103⁺ T-cell populations were also positive for the Treg-cell-specific transcription factor Foxp3 (Sakaguchi, 2005), implying that these cells do indeed perform regulatory functions (G. Zelinskyy and U. Dittmer, submitted). Co-staining experiments for all these different Treg-cell markers have revealed that two main CD4⁺ T-cell subpopulations might be involved in the suppression of CD8⁺ T-cell activity in FV infection, namely the CD25⁺ GITR⁺ CD103⁺ T cells and the CD25^– GITR⁺ CD103^– T cells. Taken as a whole, these experiments indicate that different populations of induced CD4⁺ regulatory cells play a major role in CD8⁺ T-cell dysfunction during persistent FV infection and thereby contribute to viral persistence. In HIV infection, only the population of CD4⁺ CD25⁺ Treg cells has been investigated so far and has been linked to immunosuppression. It is currently impossible to distinguish whether this T-cell population belongs to either the natural or induced Treg cells. Further Treg-cell markers will have to be analysed in future studies to provide the answer to this question with regard to chronic HIV infection.

There is increasing evidence that Treg cells, which are induced during an ongoing infection, are antigen-specific CD4⁺ T cells (Mills, 2004). Their suppressive effect, however, is not restricted to T cells of the same specificity. CD4⁺ T cells from mice persistently infected with FV suppress CD8⁺ T cell rejection of FV-induced tumours as well as antigenically distinct tumours (Iwashiro et al., 2001), indicating that pathogen-induced Treg cells can mediate a more general immunosuppression. A practical intervention that could block Treg-cell activity and reduce viral loads during chronic viral infections could prove invaluable in treating retrovirus-induced immune dysfunction.

Possible mechanisms of regulatory T-cell induction/expansion during retroviral infection
During an ongoing infection, the differentiation of naive T cells into effector T cells is controlled by APCs. The most potent population of this cell subset is that of the DC. DC induce Th-cell responses by presenting exogenous antigen via MHC class II molecules to naive CD4⁺ T cells. However, before they can efficiently present antigen, they have to mature, and this includes the cell-surface expression of MHC molecules, maturation markers and co-stimulatory molecules as well as the induction of cytokine production. Recent evidence suggests that semi-mature or immature DC induce Treg cells instead of Th cells upon presentation of antigens to naive T cells (Vlad et al., 2005). These immature DC are characterized by their low expression of co-stimulatory molecules such as CD40, CD80 or CD86 and by an impaired secretion of the cytokine IL-12 (Pollara et al., 2005). Many viruses are able to infect DC and subsequently interfere with the virus-mediated maturation process as well as with DC maturation due to other stimuli, like LPS, IFN- or CD40L (Pollara et al., 2005). This might represent a so-far unrecognized immune-escape mechanism by which viruses can induce Treg cells and subsequently suppress antiviral immune responses. In HIV it has been suggested that the virus infects DC and alters their functional properties (Steinman et al., 2003). The HIV envelope glycoprotein gp120 has been reported to reduce the capacity of DC to produce IL-12, but this did not interfere with DC differentiation (Fantuzzi et al., 2004). The accessory HIV protein vpr seems to have an even stronger effect on DC. This molecule downmodulates the expression of the co-stimulatory molecules CD40, CD80 and CD86 on DC and interferes with the expression of the DC-maturation marker CD83 (Majumder et al., 2005; Muthumani et al., 2005). In addition, HIV-1 vpr inhibits the production of IL-12 and upregulates the immunosuppressive cytokine IL-10 in DC. Furthermore, DC infected with HIV significantly reduce the activation of specific CTL (Majumder et al., 2005), indicating their immunosuppressive potential. Results from Granelli-Piperno et al. (2004) and Krathwohl et al. (2006) imply that HIV-infected DC are able to induce Treg cells that can suppress effector T-cell responses. The suppressive effect was partially dependent on IL-10 production by the Treg cells. Similar to HIV, FV productively infects DC and interferes with their maturation. This results in an impaired T-cell activation by FV-infected DC (F. Krux and U. Dittmer, unpublished results). Interestingly, activation of infected DC by immunostimulatory CpG oligodeoxynucleotides in vivo is efficient in reducing FV-induced immunosuppression (Kraft et al., 2005). Thus, the infection of DC seems to be a common feature of retroviral infections and is associated with the appearance of induced Treg cells and CTL dysfunction. An alternative mechanism for the induction of Treg cells in viral infections might be a preferential stimulation of Treg cells rather than Th cells by certain antigens of pathogens. This has at least been reported for some bacterial and parasite infections (e.g. Bordetella pertussis toxin; Mills, 2004). However, until now no retroviral antigen has been described that preferentially stimulates Treg-cell responses. Although the induction of Treg cells and their suppressive mechanisms have still not been completely understood in retroviral infections, there is increasing evidence that they play an important role in retrovirus-induced immunosuppression which might result in chronicity, a hallmark of retroviral infections. Understanding the cellular and molecular mechanisms of Treg-cell-mediated immunosuppression will certainly open new avenues for the immunotherapeutic treatment of chronic retroviral infections.

Measles virus: the T-cell silencing concept
Induction and/or expansion of regulatory Treg cells by viruses is a highly efficient strategy to prevent activation of effector T cells and this has been elegantly documented in the establishment and maintenance of persistent viral infections (Mills, 2004). In this setting, silencing of effector T cells (which, for reasons of simplicity, will be referred to as ‘T cells’) is secondary to the activation of Treg cells, a property shown for only some viruses as yet, although it is likely it will be shared by others. In this part of the review, we will focus on a quite different mode of T-cell silencing, namely that induced directly by viruses and/or their gene products. The outcome of such an interaction, on a cellular basis, could range from cell death by lysis or apoptosis to impairments of signal transduction while, at the level of the organism, T-cell depletion (including that of precursor cells), aberrant homing or malfunction would result in a generalized, antigen-unspecific immunosuppression. In humans, only two viruses are known to induce such a profound suppression of T-cell activation, namely HIV and measles virus (MV), both of which have been studied extensively in this context. This part of the review will focus on principles of T-cell silencing mainly described for MV which, however, not surprisingly, share some similarity to those seen for HIV.

In contrast to retroviral infections dealt with above, MV causes an acute, clinically apparent disease which is contracted only once in an individual's lifetime, usually during childhood. It ranks amongst the most contagious viruses known; transmission is highly efficient and morbidity/mortality rates were high in the prevaccine era and still, in spite of the availability of this efficient vaccine, more than 40 million cases of acute measles are reported annually worldwide with more than 800 000 infant deaths (Clements & Cutts, 1995). As with most, if not all, acute viral infections, measles follows a self-limiting course, with induction of cellular immunity being essential for overcoming the disease. Thus, underlying T-cell deficiencies in patients put them at high risk of severe or even fatal courses of measles. In fact, efficient activation of a virus-specific immune response leading to apparent virus clearance and followed by a long-lasting, if not lifelong, immunity to clinically apparent reinfection are well documented for acute MV wild-type infections (Griffin, 1995). Highly efficient seroconversion and long-lasting protection are also induced by mono- or trivalent (in combination with mumps and rubella) vaccination, particularly when the vaccine is implemented at the recommended two-dose strategy (Broliden et al., 1998). Vaccination is the only efficient means to combat serious sequelae of acute measles. In industrialized countries, these mainly include pneumonia, but also central nervous system (CNS) complications, one of which, subacute sclerosing panencephalitis (SSPE), relies on the only unequivocally documented persistence established by MV in the apparently immunocompetent host (Katz, 1995; Schneider-Schaulies et al., 2003a). This disease, which has been studied as the paradigm for slow virus infections of the CNS, is almost exclusively fatal, yet rare (affecting 1 in 10 000 cases of acute measles) and does not account for the majority of measles-related cases of infant death. Most such deaths follow generalized suppression of immune responses that is induced during and lasts for several weeks after acute measles in developing countries. There, exposure occurs early in infancy, when fading maternal antibodies prevent successful vaccination yet are no longer protective against wild-type MV infection (Black et al., 1986; Lennon & Black, 1986; Ryon et al., 2002; Williams et al., 1995). Further aggravated by malnutrition, secondary infections then often follow a severe or fatal course (Dollimore et al., 1997). Furthermore, persistent infections by other pathogens may be reactivated or exacerbated as a result of MV-induced immunosuppression in children and young adults (Black et al., 1996; Tamashiro et al., 1987). MV was the first pathogen noted to cause immunosuppression, almost a century ago, when von Pirquet first coined the term ‘anergy’ to describe immunological impairment in a clinical condition when he described the transient loss of delayed-type hypersensitivity responses to tuberculin during measles. Impairment of T-cell activation in vivo is probably reflected in vitro by the failure of peripheral blood lymphocytes isolated from patients to expand in response to polyclonal and antigen-specific activation (Griffin & Ward, 1993; Griffin et al., 1989; Ward et al., 1990, 1991). Further hallmarks of immunological abnormalities in measles are a marked lymphopenia and a switch from an initial Th1 to a long-lasting Th2 response (Griffin & Ward, 1993; Griffin et al., 1989; Ward et al., 1991). Since the latter is not likely to result from a direct interaction of viral gene products with the T cell but rather from that with professional APCs, this will not be considered in detail within this review.

Lymphopenia associated with MV
Measles is associated with lymphopenia affecting B cells, monocytes and neutrophils as well as CD4 and CD8 T cells, the extent of which seems to be related to the age-dependent severity of the disease (Okada et al., 2000, 2001). In contrast to B-cell frequencies, which can still be below control levels for up to 6 weeks, numbers of T cells return to normal after 10 days and the CD4/CD8 ratio remains constant over time (Arneborn & Biberfeld, 1983; Okada et al., 2001; Ryon et al., 2002).

Are T-cell precursors affected?
Prohibition of thymocyte generation and viability of or differentiation into T cells can certainly be viewed as an efficient means of affecting T-cell frequencies in the periphery. MV was found to target CD34⁺ human haematopoietic stem cells (HSCs) in vitro (Manchester et al., 2002). Though CD150, the entry receptor for all MV strains (Tatsuo et al., 2000; Yanagi et al., 2002), is expressed on and has recently been shown to be characteristic for highly purified fraction of HSCs ex vivo (Kiel et al., 2005), MV infection of these cells in vitro was possible, yet did not affect their haematopoietic capability. Rather, the ability of MV-infected stroma cells to support HSC development was impaired (Manchester et al., 2002) (Fig. 2). In contrast to the interaction of MV with HSCs, which has only been studied in vitro as yet, that with thymocytes has been addressed in various experimental settings. Thymocytes express CD150 (Aversa et al., 1997; Sidorenko & Clark, 2003) and could thus support MV entry and possibly replication. Indeed, expression of MV proteins was detectable in thymocytes (and CD4 and CD8 T cells) of mice in which transgenic expression of CD150 was driven by an Lck promoter after infection in vivo or in vitro (Hahm et al., 2003). Although likely to occur, thymocyte apoptosis was not analysed in this study. In contrast, massive thymocyte apoptosis was induced by MV in human thymus/liver xenografts in severe combined immunodeficiency (SCID) mice, where thymocytes themselves, however, remained clearly uninfected (Auwaerter et al., 1996; Valsamakis et al., 1999). It is therefore likely that thymocyte viability and/or differentiation into functional T cells is affected not primarily by direct infection but rather by infection of supporting cell types such as thymic epithelial cells, which release viral components (Valentin et al., 1999) (Fig. 2). Since CD150 ligation by antibodies can provide both activatory and inhibitory signals to lymphocytes (Sidorenko & Clark, 2003), engagement by its viral ligand, the MV haemagglutinin (H) protein, could impact on thymocyte viability as well. Interestingly, prolonged passage of avirulent MV vaccine strains in human thymic tissue enhanced their ability to cause thymocyte apoptosis (Valsamakis et al., 1999). Strikingly, however, thymic output was even increased in measles patients as assessed by TCR rearrangement excision circle (TREC) frequencies directly ex vivo, indicating that depletion of T-cell precursors may not contribute to a significant extent to T-cell lymphopenia (Permar et al., 2003) (Fig. 2). Rather, destruction of T cells by viral infection directly or indirectly, for instance by the induction of enhanced sensitivity to apoptosis, appears more likely. Indeed, evidence for the latter phenomenon was provided after CD3-ligation of T cells of patients ex vivo (Addae et al., 1995, 1998; Okada et al., 2000) (Fig. 2). Underlying mechanisms have not been identified, but clearly did not involve direct T-cell infection, as the frequency of MV-infected peripheral blood lymphocytes is very low any stage of acute disease (Borrow & Oldstone, 1995; Griffin, 1995). This is apparently in striking contrast to what has been found for the close relatives of MV, rinderpest virus (RPV) or canine distemper virus, where infected T cells were detected at high frequency in cattle or ferrets, respectively (Heaney et al., 2002; von Messling et al., 2004). T-cell depletion could occur, however, in secondary lymphoid tissues by acquisition of MV or apoptotic signals from professional APCs. In support of this hypothesis, fusion or apoptosis was found to be induced in co-cultures with MV-infected DC (Fugier-Vivier et al., 1997; Grosjean et al., 1997; Servet-Delprat et al., 2000; Vidalain et al., 2000, 2001) (Fig. 2). How transmission from DC to T cells occurs and, if so, whether it involves cell fusion is unknown, as unstimulated T cells do not express CD150 (Aversa et al., 1997). MV infection of DC may, however, not even be required for transmission, as the MV F/H glycoprotein complex was recently found to target DC-SIGN on DC and thus, as shown for HIV, MV may also be targeted to a late endosomal compartment from where it could relocate to the cell membrane (Geijtenbeek & van Kooyk, 2003; van Kooyk & Geijtenbeek, 2003). Whether T-cell apoptosis occurs in secondary lymphoid tissues in vivo, possibly induced by MV-infected DC, is unknown. Massive apoptosis, as clearly seen in lymphoid tissues of RPV-infected cattle (Stolte et al., 2002), has not been documented after MV infection to date. Giant cell formation and necrosis were reported in lymphoid tissues of MV-infected rhesus macaques, albeit to a moderate extent (Kobune et al., 1996; McChesney et al., 1989; van Binnendijk et al., 1995). Giant cell formation in hyperplastic lymphoid tissue was documented in a measles patient at autopsy; however, MV could not be detected in this area (Nozawa et al., 1994). Thus, although T-cell loss in secondary lymphoid tissues may occur, evidence for that is indirect as yet. What has, however, been measured both in infected children and vaccinees is a preferential decrease in the frequency of LFA-1^high T cells, which may indicate that these may home aberrantly to peripheral tissues (Nanan et al., 1999) (Fig. 2). In summary, in acute measles, various mechanisms may account for T-cell depletion. The contribution of T-cell loss to the generalized immunosuppression remains unclear, however, since the duration of the latter clearly exceeds that of lymphopenia.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Potential mechanisms of MV-induced lymphopenia. Only a few HSC express CD150, to low levels (indicated as light-green membrane), yet are not grossly affected by infection. Unknown components released from infected stroma cells (shown in red) interfere, however, with HSC differentiation and this may reduce the number of thymocytes. These express high levels of CD150 (bright-green membrane) and could be depleted by apoptosis, which again is independent of their infection but rather induced by viral components (N protein?) released from infected thymic epithelial cells (in red). Peripheral blood lymphocytes may undergo spontaneous apoptosis or reveal enhanced sensitivity to apoptosis upon stimulation, including that provided by MV-infected DC (shown in red) in secondary lymphoid tissues, or are depleted from the peripheral blood compartment by aberrant homing to tissues.

The N protein
The nucleocapsid (N) protein is the major constituent of both the intracellular and extracellular (enveloped) virion. In addition to complexing the viral RNA genome and the P protein with its core domain, the N protein interacts, via its C terminus, with cellular proteins such as Hsp72 and IRF-3, thereby modulating virus replication and IFN induction, respectively (tenOever et al., 2002; Zhang et al., 2002). As it is a cytoplasmic protein, the finding that soluble N protein can act as a ligand for FcRII on B cells to cause inhibition of antibody production was rather surprising (Ravanel et al., 1997) (Fig. 3). Even more striking, injection of N protein into mice was found to reduce T-cell rather than B-cell responses (Marie et al., 2001). This apparent discrepancy was solved by follow-up studies in mice which revealed that the N protein acts indirectly on T cells by modulating DC functions via interaction with FcRII, thereby preventing IL-12 production and the generation of inflammatory reactions (Marie et al., 2002, 2004). When applied exogenously in vitro, recombinant N protein causes calcium influx in thymic epithelial cells and inhibits proliferation of a variety of cell types including activated but not resting human primary T cells (Laine et al., 2003). While the ability of N protein to induce apoptosis relies on binding of its core domain to the FcRII, the ability to induce G₁ arrest was attributed to the interaction of its C-terminal tail domain with an as-yet unknown receptor (Laine et al., 2003, 2005) (Fig. 3). The C-terminal domain of N protein is, however, highly variable, and is actually therefore used for genotype assignment for MV strains. It would therefore be important to determine whether particularly MV wild-type strain-derived N proteins would inhibit T-cell proliferation via their C termini as efficiently as those of vaccine strains studied to date. MV-infected cells dying from apoptosis and/or secondary necrosis, for instance thymic epithelial cells, are considered as a source of extracellular N protein (Laine et al., 2003, 2005) (Fig. 2). Alternatively, N protein can gain access to late endosomal compartments in infected cells, where it recruits FcRII, and this allows for surface transport (where receptor-bound N protein could act in neighbouring cells) and/or release into the extracellular medium (Marie et al., 2004). Whether there is a role of N protein for T-cell silencing in vivo remains questionable. Firstly, the putative cell-surface ligand that combines N protein is only found on T cells that are already activated (Laine et al., 2003), which would confine inhibitory signals to this particular population. Secondly, a recombinant MV which expressed VSV G protein instead of the authentic MV F/H glycoprotein complex failed to induce T-cell arrest in vitro and in vivo (see below), indicating that N protein may not be essential, at least for T-cell silencing.

View larger version (18K): [in this window] [in a new window]   Fig. 3. Ligation of cellular receptors involved in MV interaction: mechanisms and consequences for lymphocyte/monocyte function. Physical and/or functional interaction of MV with cellular surface molecules [CD46 and an unknown N-protein receptor (NR) interacting with the tail domain of the N protein] or those expressed exclusively on haematopoietic cells [FcRII (interacting with the core domain of the N protein), CD150, TLR2, DC-SIGN and an unknown glycoprotein (gp) receptor (?)] also results in or helps entry into target cells or impacts on cellular functions/viability. Consequences of receptor ligation by antibodies that have not been proven to occur after MV binding are indicated in italics.

The receptor(s)
Although, at least for MV, contact-dependent T-cell arrest requires co-expression of the H protein, this arrest does not depend on the known MV entry receptors (Fig. 3). Firstly, MV F/H proteins effectively arrest proliferation of murine T cells, which do not express either of the two known H-protein-binding receptors, CD46 and CD150 (Dorig et al., 1993; Erlenhöfer et al., 2002; Naniche et al., 1993; Tatsuo et al., 2000). Secondly, CD46- or CD150-specific antibodies do not prevent silencing of human T cells (Erlenhoefer et al., 2001). Thirdly, both molecules were found to promote rather than inhibit TCR signalling (Astier et al., 2000; Sidorenko & Clark, 2003; Zaffran et al., 2001). Various effects of CD46 ligation by its natural ligands (complement components C3b/C4b), antibodies and, importantly, MV H protein on APCs or T cells have been described in molecular and functional terms; these include enhanced vulnerability to complement-mediated lysis (due to receptor downregulation) (Schneider-Schaulies et al., 1996; Schnorr et al., 1995) and modulation of inflammatory cytokine production (Marie et al., 2001, 2002) or potential interference with TLR signalling and thereby inhibition of IL-12 production (Karp et al., 1996) (Fig. 3). However, since high-affinity interaction with CD46 is a property of attenuated and not of wild-type MV strains (Hsu et al., 2001; Ono et al., 2001; Yanagi et al., 2002), the relevance of these findings for immunosuppression in vivo remains to be determined. For this, CD150 would be expected to be more important, not least because its expression is crucial for cell and tissue targeting of wild-type MV and other morbilliviruses (Erlenhöfer et al., 2002; Hahm et al., 2003; Minagawa et al., 2001; Ohgimoto et al., 2001; Schneider et al., 2002; Tatsuo & Yanagi, 2002). Within the T-cell compartment, CD150 expression is confined to activated cells (Aversa et al., 1997) and this, together with the co-stimulatory properties of the molecule, argues against the direct role of CD150 in contact-dependent T-cell silencing. Moreover, CD150 certainly does not interact with morbillivirus F proteins which are likely to harbour the effector domains (see above). Cell-surface molecules interacting with RSV or morbilliviruses include TLR2 and TLR4 (Bieback et al., 2002; Kurt-Jones et al., 2000), DC-SIGN (de Witte et al., 2006) (Fig. 3) and substance P receptor (Harrowe et al., 1990, 1992). However, these are either not expressed on human T cells (such as the TLRs and DC-SIGN) or not further analysed in terms of their ligands (substance P receptors). Moesin has also been shown to enhance MV uptake (Dunster et al., 1995; Schneider-Schaulies et al., 1995), although it does not appear to act by direct binding of MV. Thus, moesin may have an indirect role in reorganization of the actin cytoskeleton once MV has interacted with the cell surface, and this could be important for viral uptake and also for clustering of signalling receptors or T-cell plasticity.

The signal
Consistent with the observation that the release of cytokines is largely unaffected, MV contact does not affect the IL-2R-dependent activation of the JAK/STAT pathway in T cells. In contrast, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathway after IL-2R or CD3/CD28 ligation was efficiently blocked shortly after MV exposure in vivo and in vitro, while interference with activation of MAPK required longer MV exposure (Avota et al., 2001, 2004) (Fig. 4). MV is so far the only pathogen shown to interfere with activation of this particular pathway; given its important role in conveying survival and mitogenic if not oncogenic signals, some viruses activate this particular pathway (Cacciotti et al., 2005; Dawson et al., 2003; Yu & Alwine, 2002; Yuan et al., 2002). Downstream effectors of this kinase include subunits of cyclin-dependent kinases essentially involved in S-phase entry and, consequently, these were found to be deregulated in T-cell cultures exposed to or infected with MV (Engelking et al., 1999; Naniche et al., 1999). The importance of interruption of Akt kinase activation for MV-induced T-cell silencing was documented directly, as transgenic expression of a catalytically membrane-targeted active Akt kinase largely abolished the inhibitory signal (Avota et al., 2001). The regulatory subunit of the PI3K, p85, which acts upstream of Akt kinase activation, was tyrosine-phosphorylated shortly after TCR ligation in MV-exposed T cells, yet failed to redistribute to cholesterol-rich membrane microdomains (also referred to as lipid rafts), and this correlated with a lack of TCR-stimulated degradation of Cbl-b protein (Avota et al., 2004). Importantly, MV can bind and cluster lipid rafts on the T-cell surface, indicating that signalling by the F/H protein complex is probably initiated by interaction of MV with molecules within these membrane domains (Fig. 4). Most likely as a consequence of its ability to block PI3K activation, MV signalling interferes with activation of the guanosine exchange factor Vav, and this would be expected to affect cytoskeletal rearrangement occurring in response to TCR activation as well.

View larger version (32K): [in this window] [in a new window]   Fig. 4. Interference of MV glycoproteins with activation of TCR/CD28-associated signalling pathways. As a result of TCR ligation and costimulation, signalling pathways are activated that include the mitogen-associated protein kinases (MAPK) and, downstream, extracellular signal-related kinases 1 and 2 (ERK1, 2), and this is prevented 24 h after MV exposure of the cell (indicated by the F1/2/H complex interacting with an unknown receptor, ?; phosphate residues are indicated). This inhibition may partially inhibit cell activation (indicated as dashed cross). Early after exposure, MV signalling interferes with TCR/CD28-dependent degradation of Cbl-b, which is required for the release of p85 for tyrosine phosphorylation, membrane recruitment and complex formation with p110 to form the active PI3K holoenzyme. As a result of this inhibition, phosphoinositol polyphosphates are inadequately generated and, thereby, membrane recruitment and activation of the Akt kinase are essentially abolished, as is general activation of T-cell signalling from lipid rafts (indicated as dark area in the membrane) required for S phase entry and proliferation.

Summary: is there a unifying concept of virus-induced immunosuppression?
Silencing T cells and T-cell silencing are, as summarized in this review, potential strategies employed by viruses to evade ultimate control by the adaptive immune response in order to spread (for MV) and/or to establish and maintain chronic infections (for retroviruses). As outlined above, the two strategies are not mutually exclusive for the viral systems described, as retroviruses doubtlessly also encode proteins that interfere directly with activation of T cells (such as HIV gp120, vpr or nef) and MV has the ability to interfere with APC maturation and thereby might favour the induction and expansion of silencing T cells. The relative importance of the two strategies for individual viral infections may be linked directly to the nature of the infection process. In acute, self-limiting infections where viral proteins are produced in large amounts, the T-cell silencing strategy may prevail, as it may be easier to make proteins to dampen APC and T-cell activation rapidly rather than relying on a time-consuming induction of a regulatory T-cell population that needs to be activated and expanded. Viruses setting up chronic infections have to ensure that clearance during acute infection is not complete, and this may be achieved by viral proteins, but also by the expansion of natural Treg cells which downmodulate functions of effector T cells. This may help to ensure the maintenance of immune escape during chronic infection, when virus replication is usually low and the amounts of viral proteins are therefore limited.

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