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Title: Interleukin-6 Is Crucial for Recall of Influenza-Specific Memory CD4+ T Cells}
Article:
Abstract:
Currently, our understanding of mechanisms underlying cell-mediated immunity and particularly of mechanisms that promote robust T cell memory to respiratory viruses is incomplete. Interleukin( IL)-6 has recently re-emerged as an important regulator of T cell proliferation and survival. Since IL-6 is abundant following infection with influenza virus, we analyzed virus-specific T cell activity in both wild type and IL-6 deficient mice. Studies outlined herein highlight a novel role for IL-6 in the development of T cell memory to influenza virus. Specifically, we find that CD4+ but not CD8+ T cell memory is critically dependent upon IL-6. This effect of IL-6 includes its ability to suppress CD4+CD25+ regulatory T cells( Treg). We demonstrate that influenza-induced IL-6 limits the activity of virus-specific Tregs, thereby facilitating the activity of virus-specific memory CD4+ T cells. These experiments reveal a critical role for IL-6 in ensuring, within the timeframe of an acute infection with a cytopathic virus, that antigen-specific Tregs have no opportunity to down-modulate the immune response, thereby favoring pathogen clearance and survival of the host.
Introduction:
Infection with influenza virus is associated with significant mortality particularly amongst children and the elderly. The emergence of new strains, most notably avian virus H5N1, poses an increasing pandemic threat underlining the need for further studies into generation of anti-viral immunity. A consideration of how cytokines modulate cellular immune responses will facilitate a better understanding of the interplay between such pathogens and the immune system and provide rationale for enhancing vaccine efficacy. Interleukin( IL)-6, a multifunctional cytokine expressed by both lymphoid and non-lymphoid cells( reviewed in[1]), has been implicated in increasing the severity of disease in humans infected with influenza virus, including H5N1. However, murine studies indicate that IL-6 does not contribute significantly to the pathogenesis of influenza virus, since the rate of morbidity and mortality observed in mice infected with H5N1 are comparable in both wild-type and IL-6 deficient mice[2],[3]. IL-6 does however play a pivotal role in regulating the immune system – the cytokine plays a central role in resolving the innate immune response and directing the transition from innate to acquired immunity – a process that can, at least in part, be attributed to its effect on recruitment, activation and survival of different leukocyte subsets( reviewed in[4]). Although IL-6 is classically defined as a central regulator of the acute phase response, it is increasingly evident that IL-6 performs a pivotal role in influencing T cell responses. This role of IL-6 appears to be crucial for the progression of autoimmune conditions such as rheumatoid arthritis and Crohn's disease where IL-6 has been implicated in the retention of activated T-cells within the affected tissue, a finding that might provide a mechanistic basis for the highly therapeutic action of blocking IL-6R antibodies in these diseases[5],[6]. However IL-6 control of this process may represent only part of the story, since IL-6 also plays a role in orchestrating T-cell polarization, proliferation, survival, and effector function( reviewed in[4]). Collectively, these studies point to a critical role for IL-6 in directing antigen-specific T cell responses. To date however, the influence of IL-6 on development of antigen-specific T cell memory has not been explored. In this study we compared influenza-specific CD4+ and CD8+ T cell memory after infection of wild-type( WT) and IL-6 deficient( IL-6−/−) C57BL/6( B6) mice with influenza virus. The results of this study were striking and defined IL-6 as a selective regulator of long-term CD4+ T-cell memory responses, through its capacity to limit the activity of virus-specific Tregs.
Discussion:
In this study, we sought to address whether IL-6 plays a role in shaping the T cell response to influenza virus. This was considered a pertinent question since IL-6 has previously been shown to be an important survival factor for naïve T cells and to increase the frequency of antigen-specific CD4+ T cells primed in vivo[8],[11],[12]. To address this question we compared virus-specific CD4+ T cell responses in WT and IL-6−/− mice approximately three months after infection with influenza virus. The results were striking. Whilst no difference was observed in the influenza-specific CD8+ T cell responses, CD4+ T cell responses were minimal in the absence of IL-6. The impairment in the CD4+ T cell responses was observed only during the memory phase of the infection and not the primary phase. Neutralising antibody responses were comparable in WT and IL-6−/− mice though it is possible that over time, this antibody response as well as the CD8+ T cell response may wane more rapidly in the IL-6−/− mice as a result of the defect in CD4+ T cell memory[13]. A previous publication by Kopf et al. reported that IL-6−/− mice show a significant decrease in T-helper dependent CTL responses but not in those thought to be T-helper independent[14]. Similarly, the same study demonstrated that CD4+ T cell dependent IgG antibody production but not T cell-independent IgM responses were impaired in IL-6−/− mice[14]. Thus, overall, it appears that IL-6 has a major effect on the adaptive immune system primarily through its influence on the activity of CD4+ T cells. The impact of the defect in CD4+ T cell memory on clearance of influenza virus was assessed in our study. When WT and IL-6−/− mice infected with the H17 strain of influenza virus were subsequently rechallenged with the heterologous virus, PR8, we found a delay in virus clearance in IL-6−/− mice compared to WT mice. Since antibodies capable of neutralizing the PR8 virus are not present in H17-memory mice, any protection against re-infection is likely to be conferred by cross-reactive T cells. Thus, it is likely that poorer control of virus in the IL-6−/− mice is attributable to impaired CD4+ T cell memory. Thus, whilst previous reports indicate no difference in virus replication in WT and IL-6−/− mice infected for the first time with influenza virus[2],[3], protection against secondary infection may well be compromised when IL-6 is absent. Although IL-6 has been shown to act as a survival factor for CD4+ T cells, we found no evidence of increased cell death amongst lymphocytes infiltrating the lungs of IL-6−/− mice compared to WT mice either after the primary or secondary infection with influenza virus( data not shown). This observation implies that a defect in T cell survival does not account for the failure to detect an influenza-specific CD4+ T cell memory response in the IL-6−/− mice. Recently, a series of reports have highlighted that IL-6 inhibits the activity of Tregs[9],[15]. We therefore hypothesized that in the absence of IL-6 Tregs may impinge upon the development of virus-specific memory T cells. Indeed, whilst influenza-specific CD4+ T cell memory responses were consistently low in IL-6−/− mice, we found that simply depleting CD25+ cells( enriched for Tregs) from the population of splenic CD4+ T cells was enough to allow measurement of detectable anti-influenza virus responses in proliferation assays. An increase in the influenza-specific proliferative response was observed in a proportion of WT animals implying that Tregs do develop, albeit to a lesser extent, following infection of WT mice. To confirm that virus-specific Treg activity was more readily detectable in the absence of IL6, we stimulated co-cultures of CD4+CD25− cells( obtained from influenza-infected WT mice) and CD4+CD25+ cells purified from either influenza-infected WT or IL-6−/− mice with APCs infected with the virus. Suppression of the influenza-specific response was observed only in cultures containing CD4+CD25+ T cells purified from IL-6−/− mice and not in cultures containing CD4+CD25+ T cells purified from WT mice. These data indicate that IL-6 normally limits the suppressive activity of Tregs either by restricting their expansion or their suppressive capacity. Influenza virus activates DCs through engagement with TLR 3, 7 and 8[16],[17], resulting in production of large amounts of IL-6([18] data not shown). Thus, influenza-infected DCs may represent at least one relevant source of IL-6 in the system under study here. Our finding that IL-6 deficiency promotes the activity of antigen-specific Tregs parallels observations made in a murine model of asthma where blocking the mIL-6R with specific antibodies led to an increase in the number and suppressor activity of FoxP3 positive cells in the lungs of the experimental mice[15]. This report indicated that IL-6 activated Tregs via the mIL-6R whilst IL-6 responses in conventional effector T cells were elicited via its soluble receptor( sIL-6R), a process known as IL-6 trans-signaling( reviewed in[19]). However due to lack of reagents available to selectively manipulate IL-6 trans-signaling over the course of the 8–10 week viral infection, it is difficult to gauge whether a dual-mode of IL-6 signaling influences the outcome of the anti-influenza response. Our findings do however support the premise that the major target of IL-6 activity in our influenza model is the Treg population rather than conventional CD4+ T cells. Whilst the CD4+ memory T cell response is diminished in IL-6−/− mice, due to the suppressive effect of Tregs, the memory CD8+ T cell response is unimpaired. This observation implies that CD4+ and CD8+ T cells differ in their susceptibility to suppression by Tregs. It is not clear why this should be the case since CD8+ T cells can be suppressed by Tregs under some circumstances[20]. Ultimately, a better understanding of how Tregs exert their suppressive effects in vivo will help clarify this issue. Development of virus-specific Tregs in the absence of IL-6 may be explained by the recently described role of IL-6 in steering the commitment of naïve CD4+ T cells. Bettelli et al. demonstrated that IL-6 suppresses development of Tregs induced by TGFβ[10], a cytokine shown to facilitate differentiation and expansion of Tregs[21],[22]. With this in mind, it is possible that TGFβ is also produced during the immune response to influenza virus, which in the absence of IL-6 promotes expansion of Tregs. Bettelli et al. also showed that a combination of IL-6 and TGFβ directs the commitment of naïve T-cells towards an IL-17-secreting CD4+ T-helper( Th-17) population[10]. We saw no evidence of IL-17-secreting CD4+ T( Th-17) cells in the primary or secondary response to the influenza infection ruling out an essential role for these in development of virus-specific CD4+ T cell memory in WT mice. Collectively, the data presented in this study point to a critical role for IL-6 in promoting memory CD4+ T cell responses. This may be due in part to the activities of IL-6 in promoting survival, proliferation and migration of antigen-specific T cells but as described in this study, a major pathway through which IL-6 promotes CD4+ T cell memory is through its inhibitory effect on virus-specific Tregs. The involvement of Tregs in infectious disease is curious. Many groups have studied Tregs in chronic infection and have, in some cases, attributed their involvement to a need for limiting pathogen-induced immunopathology[23],[24]). In the case of acute infection, the question that arises is why should Tregs be involved at all? Results of a recent study investigating the turnover of human Tregs imply that Tregs can arise from the antigen-specific memory T cell pool and are relatively short-lived compared to other T cells[25]. These findings led the authors to propose that antigen-specific Tregs facilitate resolution of an immune response without compromising the ability of the immune system to respond to a second challenge with the same antigen. These data imply that Tregs limit a primary T cell response without necessarily impinging on a memory response. Our findings imply that an absence of IL-6 favors conditions that enhance survival of Tregs allowing them to persist and inhibit the memory T cell response. The precise nature of these conditions remains to be defined. However it is conceivable that the cytokine milieu induced in response to antigenic challenge in the absence of IL-6 may influence the outcome of the response. In consideration of the question “why should Tregs play a role in acute infections? ”- we would suggest that production of IL-6 by virus-infected cells serves two purposes – to promote priming of antigen-specific effector T cells, and to inhibit priming of antigen-specific Tregs thereby ensuring, within the time-frame of an acute infection, that antigen-specific Tregs have in fact, no opportunity to play a role. Although the concerted activity of many arms of the immune system contribute to pathogen clearance, CD4+ T cells play a central role both in promoting and coordinating these activities and in facilitating long-term CD8+ T cell memory and B cell memory. Induction of a robust CD4+ T cell response is therefore likely to be critical to the success of any vaccine strategy. The results of this study imply that co-administration of IL-6 with an anti-influenza virus vaccine will promote development of protective immunity through optimal induction of a virus-specific memory CD4+ T cell response.
Influenza virus poses a serious global health threat , particularly in light of newly emerging strains such as the avian virus H5N1 . The generation of cell-mediated vaccines against influenza virus requires an understanding of mechanisms underlying effective virus-specific T cell memory . This study explored the impact of a cytokine , interleukin-6 ( IL-6 ) , on generation of effective influenza-specific T cell memory . This cytokine was considered important based on previous studies revealing its role in promoting survival and activity of conventional T cells whilst inhibiting the activity of T cells involved in dampening down immunity ( regulatory T cells ) . We found that the activity of a subset of influenza-specific memory T cells ( CD4+ T cells ) was diminished in the absence of IL-6 due to the inhibitory effects of regulatory T cells—an effect that compromised protective anti-viral immunity . Since a robust CD4+ T cell response is likely to be central to the success of a vaccine against influenza virus , these findings highlight the importance of IL-6 in promoting effective cell-mediated immune responses , thereby facilitating successful virus clearance .