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Carter Immunology Center, Departments of Pathology and Microbiology, University of Virginia, Charlottesville, Virginia
Correspondence and requests for reprints should be addressed to Thomas J. Braciale, Beirne B. Carter Center for Immunology Research, University of Virginia Health System, Box 801386, MR4 Bldg., Charlottesville, VA 22908. E-mail: tjb2r{at}virginia.edu
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ABSTRACT |
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 TOP ABSTRACT WHAT DOES RSV DO...HOW DO T CELLS...WHAT ARE THE IMPLICATIONS...REFERENCES |
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Key Words: injury • respiratory syncytial virus • T cells • vaccine
Respiratory syncytial virus (RSV) is a lipid-enveloped, negative-strand RNA virus and a member of the family Paramyxoviridae. RSV is a major cause of morbidity from respiratory infections in infants and very young children (< 1 year old), with bronchiolitis and pneumonia representing the most severe manifestations of RSV infections. In this age group (< 1 year old), RSV infection results in an estimated 85,000–225,000 pediatric hospitalizations per year in the United States alone (1, 2). Furthermore, even though the impact of RSV infection on infant morbidity in underdeveloped countries cannot be accurately estimated, it is likely to be considerable. In addition, this virus is a well recognized cause of morbidity/mortality from pneumonia in immunosuppressed transplant patients, and has been increasingly appreciated as a significant cause of morbidity from respiratory infection in the elderly (3, 4).
RSV is also one of several viral agents which have been linked to the development or exacerbation of airway hyperresponsiveness (i.e., wheezing episodes) in childhood and adolescence. In considering the contribution of RSV to the development/expression of childhood asthma-like syndromes, it is useful to distinguish between two separate issues in airway hyperreactivity: RSV's potential role in the etiology of the condition; and RSV infection resulting in the exacerbation of the condition (when the etiological basis for childhood asthma lies elsewhere). In the latter case, an increasing large body of evidence suggests that RSV is one of a number of viral agents that can trigger wheezing in asthma-prone individuals with Rhinovirus infection—representing perhaps a more frequent and therefore more important stimulus compared with RSV for the development of wheezing episodes.
In the former case (i.e., an etiologic role of RSV infection in childhood asthma), there is at least one report suggesting an association between severe RSV infection (i.e., the development of severe acute bronchiolitis) in early infancy, and asthma development in later life (5). This link between early severe RSV infection and the predisposition to childhood asthma development has, however, not been observed in other longitudinal studies (6). Rather, individual differences in airway structure/architecture, coupled with the multiple genetic factors linked to asthma development/exacerbation, may play a dominant role (in childhood) in the etiology of asthma and in the subsequent development of wheezing episodes triggered by respiratory virus infections (7). The development of severe acute RSV disease in early infancy may simply serve as a marker for those individuals that are genetically predisposed to asthma development in later life. Nevertheless, the likely contribution of T cells (in particular, Type 2 cytokine-producing CD4+ Th2 T cells) to the development of RSV vaccination–associated enhanced disease after RSV infection of vaccinated individuals (in both humans and animals, discussed below), as well as a strong association between CD4+ Th2 responses and asthma development, suggest a potential and as yet ill-defined role of RSV in the etiopathogenesis of asthma as well as in the triggering of wheezing episodes in individuals with asthma.
Although RSV has been recognized as an important human pathogen for more than 40 years, there is no clinically licensed, effective RSV vaccine. Because the major target population for such a vaccine would be young infants (i.e., children between the neonatal period and 1 year of age), effective vaccination is hampered by the problems inherent in immunization in early infancy—that is, the relative immaturity of the immune system, and the presence of transferred maternal antibody. However, two novel features of RSV infection impact both on the development of a successful vaccine, and perhaps on disease severity during RSV infection. First, unlike many other respiratory viruses, primary RSV infection does not confer effective immunity against subsequent infections. Individuals previously infected with RSV can be subsequently reinfected (within months) with an identical or antigenically closely related virus (8, 9). Antigenic variation (a strategy employed by Influenza and Rhinovirus to evade the adaptive immune response) does not appear to play a critical role in susceptibility to reinfection with RSV, as antigenic variation in the major viral protein targets of neutralizing antibody (i.e., the RSV-G and RSV-F surface proteins) is not extensive enough to allow for immune escape. Nevertheless, with repeated infections, the severity of clinical RSV disease diminishes, and infection may even be asymptomatic—suggesting that protective immunity can progressively develop over time (until the geriatric period when immune senescence may result in severe infections). Second, vaccination of seronegative individuals with an inactivated RSV virion vaccine results not in protection against subsequent natural infection, but rather in enhanced systemic illness and pulmonary injury (10, 11).
These two features of RSV infection (i.e., susceptibility to repeat infection and enhanced disease during a recall/memory adaptive immune response to infection after vaccination) suggest that RSV employs one or more novel mechanisms of immune dysregulation to propagate and maintain a reservoir within the human population.
This article will focus exclusively on the interaction of RSV with T lymphocytes. In the first section (WHAT DOES RSV DO TO T LYMPHOCYTES?), we will review the evidence that RSV infection of the respiratory tract can inhibit/alter the activation of T cells, and thereby suppress the expression of T cell effector activity—because this effect of RSV may have important implications for the development of severe acute disease during primary RSV infection. In the second section (HOW DO T CELLS BEHAVE DURING RSV INFECTION?), we will examine the behavior of T cells—in particular, the trafficking of memory T cells responding to RSV infection during the development of vaccine-associated enhanced pulmonary disease. This information (on T cell behavior) is providing insight into the interplay of T cells in regulating the adaptive immune response to RSV, and may provide new information on the function of T cells in allergic airway disease.
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WHAT DOES RSV DO TO T LYMPHOCYTES? |
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TOPABSTRACTWHAT DOES RSV DO...HOW DO T CELLS...WHAT ARE THE IMPLICATIONS...REFERENCES |
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In addressing the question "What does RSV do to T lymphocytes?," it is useful to point out a potential paradox concerning the role of T cells in the response to RSV infection—that is, although T cells (both CD4+ and CD8+) appear to play an important role in viral clearance, studies in experimental models also indicate that effector T cells responding to RSV infection also contribute to injury development. That the adaptive host immune response contributes to the overall inflammatory response (and, therefore, injury at the site of infection) during virus clearance is generally accepted as an unavoidable consequence of pathogen elimination. In the case of RSV infection, excessive pulmonary injury temporally associated with the mobilization of the T cell response to infection in the lungs could reflect a deficit in the induction of an effective effector T cell response to RSV, a delay in the tempo of T cell activation, or an alteration in the expression of T cell effector activity in the infected respiratory tract (induced by the virus). As discussed below, one or more of the effects may be manifestations of RSV-induced immune dysregulation.
Early studies in humans, where peripheral blood mononuclear cells (PBMC) were co-cultured with RSV, revealed that the interaction of PBMC with virus resulted in the release of soluble factor(s) from cultured cells, which could suppress in vitro T cell activation (14). The monocyte/macrophage fraction of the PBMC was the apparent source of this suppressive activity; and number of soluble factors (e.g., interleukin [IL]-10, transforming growth factor-ß, etc.) released as a result of mononuclear cell interaction with the virus could account for this suppressive effect.
More compelling evidence for a direct effect of a specific RSV gene product on T cell activation has come from recent in vitro studies in the human. This analysis suggests that the direct encounter of naive human T cells with the RSV-F glycoprotein results in the inhibition of T cell activation (15). The mechanism underlying this inhibitory effect of the F protein on T cell activation has not been, as yet, elucidated. However, F protein–induced suppression of T cell activation would also be expected to affect the magnitude of the RSV-specific T cell response, and therefore affect the efficiency of virus clearance from the infected respiratory tract. This would, in turn, result in a prolonged inflammatory response in the lungs, and enhanced pulmonary injury. If, as these in vitro studies suggest, the F protein can act on any T cells encountering the virus and/or F-expressing virus-infected cells, then antigen-nonspecific transient immune suppression would be a feature of RSV infection—a finding not documented during natural RSV infection in humans.
Available evidence from both humans and experimental animal studies implicates dendritic cells (DCs) as the primary antigen-presenting cells necessary to activate antigen-specific naïve T cells (16). Although not as yet documented in the human studies, results from experimental models of respiratory infection suggest that respiratory DCs likely carry viral antigen from the respiratory tract to the lymph nodes draining the respiratory tract, where DCs encounter and subsequently activate naïve virus-specific T cells; so RSV infection of DCs, and the resultant display of the F protein on the infected DC surface, could result in F-induced suppression of T cell activation within the draining lymph nodes. RSV infection of DCs has also been reported (under several experimental conditions) to inhibit the secretion of effector cytokines, notably IFN-
, by primary T cells responding to antigen-pulsed RSV-infected DCs (17–19). In these instances, it is the expression of effector activity by activated T cells, rather than the induction of the T cell response, that is impaired by RSV.
Studies from our laboratory in the murine model of RSV infection of the respiratory tract have revealed a second level of dysregulation of T cell function by RSV (i.e., at the level of expression of CD8+ CTL effector function) in the infected respiratory tract (20, 21). During an analysis of the induction of the CD8+ T cell response to a specific RSV protein (i.e., RSV M2.1), we employed MHC class I tetramer staining (22) to enumerate and examine the kinetics of RSV M2–specific primary CD8+ CTL responses in the lungs. We demonstrated a significant RSV-specific CD8+ T cell response in the lungs during primary infection by tetramer staining. This finding suggested that (in the mouse at least) the initial events in the activation and proliferative expansion of the naive RSV-specific CD8+ T cells were normal. However, when activated CD8+ T cell effector cells were isolated from the lungs, then examined for the capacity to release the effector cytokine IFN-, less than 50% of the RSV M2–specific T cells were capable of releasing this cytokine in response to antigen (20). Importantly, this defect in effector function was only detected in CD8+ T cells in the infected lungs—whereas effector CD8+ T cells that had migrated from the draining lymph nodes to other secondary lymphoid organs (e.g., the spleen) had no deficit in effector function.
In addition to the defective response of effector CD8+ CTL in the lungs during the acute phase of infection, we also noted a rapid loss (decrease in frequency) of RSV-specific memory CD8+ T cells in the lungs during the resolution phase of infection. This finding was noteworthy in view of the data in human RSV infection suggesting a lack of durable immunologic memory generation after infection with this virus. These findings in the murine model were particularly intriguing, as they suggested that RSV may dysregulate the expression of effector activity by CD8+ CTL and suppress memory development only at the primary site of RSV replication in the respiratory tract. Thus, sampling of RSV-specific memory CD8+ T cells circulating in the peripheral blood of previously infected individuals would not reveal any defect in T cell activation or effector T cell generation. Our data further suggested that this altered effector activity resulted from a defect in T cell signaling through the T cell antigen receptor. We have gone on to evaluate a range of CD8+ CTL effector activities exhibited by the T cells infiltrating the RSV-infected lungs. Strikingly, the extent of inhibition/suppression differs from different CD8+ T cell effector activities (J. Castillio and T. Braciale, unpublished observations). For example, cell-mediated (perforin-dependent) cytotoxicity is substantially more inhibited than release of T cell effector cytokines like tumor necrosis factor-
. The potential significance of these findings is discussed below.
These converging lines of evidence, from in vitro and in vivo analyses in both the human and the mouse, strongly suggest that RSV may dysregulate T cell function at the level of T cell activation, or at the level of effector activity expression—or at both levels. The data (from both the human and the mouse) indicating RSV-mediated alteration in T cell effector function is particularly intriguing, as it indicates a potential mechanism of adaptive immune-mediated injury linked to RSV replication in the respiratory tract. Specifically, it is likely (although not formally demonstrated in humans) that RSV-specific effector T cells play a critical role in virus clearance from the respiratory tract. If the expression of different effector activities by responding T cells infiltrating the RSV-infected respiratory tract are differentially affected by RSV, this may result in the preferential suppression of T cell effector activities that are critical for virus clearance (e.g., cell-mediated cytotoxicity) with the retention of effector activities associated with proinflammatory responses (e.g., tumor necrosis factor- release). The likely outcome of this RSV-induced selective T cell dysregulation would be delayed virus clearance from the respiratory tract (and/or prolonged survival of virus infected cells), resulting in sustained expression of inflammation/injury-inducing effector activities from the responding T cells in the respiratory tract during primary RSV infection and the development of severe acute disease.
The test of this, or related mechanisms of RSV-induced T cell dysregulation and their impact on RSV-associated pulmonary injury, would likely require an analysis of the function of effector T cells taken directly from the respiratory tract of infected individuals. This represents a particular challenge for investigators who must carry out such studies in very young, very sick infants. Future studies should be directed toward: (1) defining if such a deficit exists in the expression of effector activity by T cells removed from the RSV-infected respiratory tract; and (2) determining the contribution of specific RSV gene products to the development of pulmonary injury and of cells of the adaptive immune system—in particular to dysregulation of the function of cells of the adaptive immune response.
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HOW DO T CELLS BEHAVE DURING RSV INFECTION? |
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TOPABSTRACTWHAT DOES RSV DO...HOW DO T CELLS...WHAT ARE THE IMPLICATIONS...REFERENCES |
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Two distinct mechanisms have been proposed to account for vaccine-induced enhanced injury to RSV. One mechanism involves the generation of a memory CD4+ T cell response to vaccination, which is skewed toward the development of a preferential Th2 response with subsequent RSV infection, whereas the other mechanism implicates immune complex deposition in the respiratory tract of vaccinated individuals after RSV infection. Evidence supporting each mechanism has been reported (25, 26). In the early failed human trials (with formalin-inactivated RSV), alum was used as an adjuvant to enhance the response of the vaccine. Alum is now well recognized as an adjuvant that facilitates naive CD4+ T cell differentiation along the Th2 lineage pathway. Therefore, the exaggerated memory CD4+ Th2 effector response observed during RSV infection of infants that had been previously vaccinated with inactivated RSV could, in part, reflect the contribution of the alum adjuvant. In considering the role of CD4+ Th2 T cells in vaccine-induced pulmonary injury, it is first useful to consider the potential contribution of type 2 cytokines to disease severity in children hospitalized for acute primary RSV bronchiolitis. Published reports demonstrate both the presence (27, 28) and absence (29) of type 2 cytokines in the respiratory tract of these children. Thus, although no clear-cut consensus emerges from these clinical studies, it is likely that effector CD4+ Th2 T cells do not play a dominant role in the development of severe disease during primary RSV infection of seronegative individuals. Indeed, as noted above, there is a body of information implicating products of the innate immune system in the development of severe disease in primary RSV infection (12, 13); so how the development of a defective adaptive CD8+ T cell response during primary infection modifies/amplifies disease severity remains unknown. However, in the case of vaccinated individuals, a CD4+ T cell response skewed toward Th2 cytokine production (after challenge RSV infection) may contribute prominently to the disease produced.
It is noteworthy that the enhanced injury associated with the formalin-inactivated RSV vaccine was not only observed in the early human vaccine trials, but was also reproduced in experimental models of RSV infection in several species (30–34). If a memory CD4+ T cell response skewed toward Th2 cytokine production is central to the etiopathogenesis of RSV vaccine–induced enhanced disease, the demonstration of this immune-mediated injury in diverse species suggests that RSV may have a unique propensity to drive memory CD4+ T cell differentiation toward a Th2 type effector response in the respiratory tract during infection of vaccinated individuals. The properties of RSV that result in this effect on T cells are currently unknown. The lack of knowledge on this point remains a major unresolved issue in the immunobiology of RSV infection. We have, however, begun to understand (at least in model systems) the interplay between T cells that regulates the development/expression of vaccine-induced enhanced disease; and this topic is discussed below.
Immunization with intact inactivated RSV vaccine will activate B cells (i.e., elicit a neutralizing antibody response), and will activate CD4+ T "helper" cells (i.e., trigger the CD4+ T cell effector/memory response); but the activation of CD8+ T cells will be weak. Furthermore, when an intact virion vaccine is used for immunization, the contribution of specific virion gene products to the development of enhanced disease cannot be easily evaluated. Fortunately, the availability of recombinant vaccinia viruses expressing individual RSV proteins has advanced our understanding of the interplay of T cell subsets in the development of enhanced injury. These recombinant vaccinia vectors (used in lieu of the intact virion for vaccination) have helped to establish the role of individual RSV gene products in priming for the enhanced response to subsequent RSV infection. Studies in the murine model revealed that, among the RSV proteins used for priming (e.g., F, N, M2, G) only the vaccinia expressing RSV-G resulted in pulmonary eosinophilia after challenge intranasal RSV infection (35–37). Further analysis revealed a difference in the generation of memory T cell responses by individual RSV gene products that could be recalled by RSV challenge infection (35, 38). RSV-G immunization selectively generated only a memory CD4+ T cell response, with no detectable recall memory CD8+ T cell response to subsequent infection. In contrast, other RSV proteins (e.g., F, N, M2) stimulated both CD4+ and CD8+ T cell memory populations.
Immunization with recombinant vaccinia virus should, like natural infection with live RSV, stimulate both CD4+ and CD8+ T cells directed to the expressed RSV protein. So the enhanced injury and pulmonary eosinophilia observed in G-primed mice after challenge infection might be linked to the selective generation of a G-specific memory CD4+ T cell population during priming (i.e., without the concomitant generation of memory CD8+ T cells). This hypothesis was appealing because (as discussed above) immunization with intact inactivated RSV (or purified RSV proteins administered in adjuvants) would stimulate a vigorous CD4+ T cell memory population with minimal stimulation of virus-specific CD8+ T cells since these forms of viral proteins (unlike the proteins expressed by recombinant vaccinia vectors) would not efficiently enter the MHC class I antigen presentation pathway to stimulate a memory CD8+ T cell response. We tested this hypothesis in experiments in which animals were primed with a vaccinia virus expressing an engineered chimeric full-length G-protein construct encoding a 10–amino acid CD8+ T cell epitope from the RSV-M2.1 protein. Mice primed with this chimeric G-protein construct exhibited no lung eosinophil accumulation after challenge RSV infection (39). Thus, the vaccination of mice with an RSV-G protein (capable of generating both memory CD4+ T cells [to G] and memory CD8+ T cells [to the M2.1 epitope]) resulted in the suppression of the development of a memory CD4+ Th2 effector response after challenge infection.
The concept that the presence of responding CD8+ T cells might alter CD4+ T cell differentiation away from CD4+ Th2 effector generation in the environment of the RSV-infected lung was appealing. In particular, it provided an explanation for the lack of pulmonary eosinophilia during primary and subsequent RSV infections (i.e., during natural RSV infection, both virus-specific CD4+ and CD8+ T cells are generated). Therefore, the propensity of CD4+ T cells to differentiate into Th2 effector cells during RSV infection might be suppressed by the presence of CD8+ T cells simultaneously responding to RSV infection.
But what could be the mechanism by which responding CD8+ T cells might modify CD4+ T cell differentiation away from Th2 effector T cell generation in such a way? Unfortunately, that possible mechanism remains undefined. A large body of evidence emerging over the past decade indicates that the cytokine milieu in which CD4+ T cells activate/differentiate controls the development of these T cells into Th1 or Th2 effector cells (40, 41)—with IL-12/IFN- driving CD4+ Th1 generation, and IL-4 playing a pivotal role in directing CD4+ Th2 differentiation. In the murine model of enhanced RSV disease, one report has implicated the early production of IFN- by responding CD8+ T cells as a critical factor in controlling (suppressing) the expression of Th2 cytokines by responding CD4+ T cells (42). However, this mechanism of CD8+ T cell regulation of CD4+ T cell differentiation has not been supported in other studies (39, 43).
In considering how, in previously vaccinated or infected individuals, RSV-specific memory CD8+ T cells would regulate the differentiation (and hence, the response) of RSV-specific memory CD4+ T cells, it is equally important to consider where this regulation and this putative CD8+/CD4+ T cell interaction might occur. We have begun to address the "where" of this CD8+/CD4+ T cell interaction in the murine model of RSV-G–induced enhanced disease. There is a compelling body of evidence to suggest that naive CD4+ (and CD8+) T cells responding to infection at a peripheral site/body surface (e.g., the respiratory tract), first encounter pathogen-derived antigen within the secondary lymphoid organs (typically lymph nodes) draining the site. As a result of this encounter with antigen (in the form of professional antigen-presenting cells, such as DC, displaying processed peptide fragments of the microbial product), naive T cells will (over a 3- to 5-day period) activate, proliferate, and differentiate into mature effector cells that leave the draining lymph nodes and migrate to the site of infection. This activation/differentiation program gives rise not only to pathogen-specific effector T cells, but also to two types of memory T cells—so-called central memory (TCM) and peripheral/effector memory (TEM) T cells (44). TCM circulate from the blood into secondary lymphoid organs, then exit lymph nodes/spleen through the lymphatic system and reenter the blood stream to begin the recirculation process. TEM are believed to reside primarily in peripheral nonlymphoid tissues (e.g., the respiratory tract). One or both of the memory CD4+ T cell subsets would orchestrate the enhanced injury observed with vaccine-induced RSV disease; and one or both of the corresponding TCM or TEM memory CD8+ T cells populations presumably serve(s) to modulate CD4+ T cell differentiation.
We have focused our efforts on defining the site(s) where memory CD4+ T and CD8+ T cells interact to control the expression of CD4+ Th2 effector activity in the lungs. There are two likely sites where this interaction would occur: (1) at the site of RSV infection (i.e., the respiratory tract); or (2) in the lymph nodes draining the respiratory tract. In the case of the respiratory tract, CD4+ and CD8+ TEM resident in the respiratory tract would interact directly in the respiratory tract in response to RSV infection; as a result of this interaction, these TEM could modify the differentiation of effector CD4+ T cell progeny. In the case of the draining lymph nodes, RSV-specific CD4+ and CD8+ TCM cells would presumably be interacting in the draining lymph nodes during the initial encounter of these TCM with viral antigen. Alternatively, proliferating CD4+ and CD8+ T cells (TCM progeny) produced in the nodes could migrate from the draining lymph nodes to the infected respiratory tract, where these effector CD8+ T cells could alter the effector CD4+ T cells cytokine response, leading to the suppression of CD4+ Th2 effector cell development. To approach this issue of T cell interaction site(s), we need to identify where memory CD4+ T cells activate, proliferate, and differentiate (i.e., in the draining nodes and/or in the lungs?).
We have initiated studies to determine "where" (i.e., the site of) RSV-specific memory CD8+ T cells interact with memory CD4+ T cells to regulate their effector response. Our starting point was to examine the generation kinetics of the RSV-G–specific CD4+ T cell response in the lungs of G-primed mice undergoing challenge RSV infection. We observed that activated G-specific memory CD4+ effector T cells rapidly accumulate in the infected lungs by Day 3 after infection and reach maximum accumulation by Day 5 after infection (45). This accelerated accumulation of effector CD4+ T cells in the lungs is consistent with the more rapid response of memory T cells (either TCM or TEM) to antigen encounter. However, it was not possible to discern the lineage the effector CD4+ T cell progeny. Did they arise from the proliferative expansion of G-specific, lung resident TEM, or from TCM activating and proliferating in the draining lymph nodes?
One novel feature of the memory CD4+ T cell response in the mouse to RSV-G provided the opportunity to further explore the site of memory CD4+ T cell activation and proliferative expansion. Briefly, we observed that the RSV-G–specific memory CD4+ T cell response is oligoclonal—that is, more than 50% of responding T cells recognize a single immunodominant site on the G protein (residues 183–195), and use a single T cell receptor ß-chain variable region product (i.e., Vß14) in the T cell receptor complex used for RSV-G protein recognition (45, 46). The expression of the Vß14+ T cell receptor (TCR) by the majority of responding CD4+ T cells in the lungs served as a marker to identify the CD4+ T cells responding to challenge infection and to track the site of T cell activation/proliferation. These ongoing studies have revealed the following: (1) memory CD4+ T cells undergo extensive proliferation in the infected lungs; (2) the CD4+ T cells accumulating in the lungs between Days 3 and 5 of challenge infection differentiate during proliferative expansion into cytokine-producing effector T cells; (3) RSV-G–specific CD4+ TEM resident in the lungs of vaccinated animals are present at low frequency at the time of challenge infection, and do not contribute to the proliferative expansion of CD4+ T cells observed between Days 3 and 5 of challenge infection; and (4) RSV-G–specific CD4+ TCM are the source of the effector T cells accumulating in the lungs. Importantly, our results suggest that, in contrast to naive T cells that proliferate/differentiate in the draining lymph nodes, RSV-specific TCM, which recirculate from the blood through the lymph nodes, encounter RSV antigen within the draining nodes, then rapidly activate (within hours of antigen contact) and immediately migrate from the lymph nodes to the site of RSV infection, where the TCM undergo proliferative expansion of and differentiation into effector cells.
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WHAT ARE THE IMPLICATIONS OF THESE FINDINGS? |
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TOPABSTRACTWHAT DOES RSV DO...HOW DO T CELLS...WHAT ARE THE IMPLICATIONS...REFERENCES |
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These results in a model system of RSV infection may also have a more general implication for the development/expression of allergic disease in the respiratory tract—that is, memory CD4+ T cells (presumably TCM) directed to and responding to aeroallergens would be susceptible to modulation during their differentiation into effector T cells in the respiratory tract. Although this implication begs the fundamental issue of why CD4+ T cells would respond to innocuous antigens introduced into the respiratory tract by generating CD4+ Th2 effector T cells, these findings suggest that alteration of the respiratory tract environment by therapeutic intervention could suppress the development of allergic Th2 effector T cell responses to these aeroallergens.
Summary
It is becoming increasingly clear that RSV infection of the respiratory tract uniquely affects the host response in the airways. Studies by us and others in experimental models suggest that RSV can affect both the expression and the type of effector activity of T lymphocytes responding to RSV infection in the milieu of respiratory tract. It is also becoming increasingly clear that the complex interplay of the innate and adaptive immune systems in response to RSV plays a pivotal role in the development of severe acute pulmonary disease during RSV infection. Certainly, what RSV infection of cellular targets in the respiratory tract (e.g., respiratory epithelial cells, etc.) does to the viability and cytokine/chemokine response of these infected cells will have a direct impact on what RSV does to responding T cells. Likewise, how RSV infection alters the milieu of the respiratory tract will impact on what T cells do in response to infection, and how the interaction of different T cell subsets (i.e., CD4+ T cells, CD8+ T cells, TCM, TEM) can modulate the outcome of infection. Understanding the interplay between components of the host response to RSV will be essential for the development of an effective vaccine against RSV.
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FOOTNOTES |
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(Received in original form March 21, 2005; accepted in final form April 27, 2005)
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TOPABSTRACTWHAT DOES RSV DO...HOW DO T CELLS...WHAT ARE THE IMPLICATIONS...REFERENCES |
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