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GEN News Highlights : Feb 10, 2012
Interleukin Released on Viral Infection Directly Stimulates CTL Response
Alarmin molecule IL-33 triggers CTL expansion in mice to clear lymphocytic choriomeningitis virus.!--h2>
Scientists have demonstrated how inflammatory factors released by necrotic cells as a result of viral infection directly trigger the expansion of cytotoxic CD8+ T lymphocytes (CTLs). An international team led by researchers at the University of Geneva found that IL-33 is required for generating protective CTL responses to RNA and DNA viruses in mice.
Their work showed that animals deficient in the interleukin or receptor ST2 fail to mount strong CTL responses following viral infection, and that these responses are a direct result of IL-33 recognition by the CTLs themselves. Daniel D. Pinschewer, M.D., and colleagues report their findings in ScienceExpress in a paper titled “The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses.”
Pathogen-associated molecular patterns (PAMPs) are molecules displayed by related groups of microorganisms that trigger the adaptive immune responses to infection. PAMPs differ from endogenous molecular patterns, or alarmins, which signal tissue injury and are classified as damage-associated molecular patterns (DAMPs). What isn’t yet known, the authors write, is whether alarmins also help enhance antiviral defense mechanisms.
To look at this further, the researchers looked more closely at the inflammatory signals released by spleen cells in mice infected with the lymphocytic choriomeningitis virus (LCMV). They carried out genome-wide cDNA expression analysis of total spleen tissue from LCMV-infected animals, and compared with uninfected controls. Of the panel of interleukins and proinflammatory cytokines evaluated, interferon-γ (IFN- γ) and IL-33 were the most upregulated, as was the IL-33 receptor ST2 (also known as T1, or IL1RL1).
IL-33 is naturally expressed by nonhematopoietic cells including fibroblasts, epithelial, and endothelial cells. In these cells IL-33 complexes with chromatin and plays a role in modulating gene expression. However, the cytokine is also released from cells in a bioactive proinflammatory form as a result of necrosis, and is thus classified as an alarmin. In this situation IL-33 binds to and signals through ST2.
What the researchers wanted to find out was whether IL-33 also plays a role in stimulating the production of antiviral cytotoxic T lymphocytes. When they tested this by infecting IL-33-deficient (IL33-/-) mice with LCMV, the results were striking. Compared with control infected mice, the IL33-/- mice generated 90% fewer CTLs that responded to the major LCMV epitope GP33, and the level of any epitope-specific CTLs was reduced by more than 75%.
Tests in mice expressing a decoy receptor for IL-33 also mounted defective CTL responses to LCMV epitopes after viral infection, as did animals lacking the ST2 receptor. STR-deficient mice didn’t, however, exhibit any detriment in LCMV-neutralizing antibody responses to LCMV infection when compared with wild-type controls.
The results to date indicated that IL-33 was released by cells in the spleen and signaled through ST2 to amplify antiviral CTL responses. Similar reductions in CTL responses and antigen-specific cytotoxicity were exhibited by STR-deficient mice following infection with either the DNA virus MHV-68 (LCMV is a RNA virus) or a wild-type vaccinia virus (VV). In contrast, infecting STR-deficient mice with either a nonreplicating adenovirus-based vaccine vector, a replication-deficient LCMV-based vaccine vector, or an attenuated VV-based vector didn’t impact adversely on CTL responses.
The next stage was to determine which cells were detecting infection-related release of IL-33 as a trigger for boosting antiviral CTL responses. Experiments in lethally irradiated, LCMV-infected mice given transplants of equal amounts of wild-type and ST2-deficient bone marrow suggested that virus-reactive CTLs directly respond to IL-33 as a result of ST2 signaling, and are triggered to undergo expansion. In fact, by day six after LCMV infection, ST2 expression was seen on up to 20% of virus-specific CTLs.
IL-33 signaling through ST2 involves the adaptor protein MyD88 and downstream phosphorylation of p38 MAP kinase. Further studies in irradiated, LMCV-infected mice adoptively transferred with T cell receptor-transgenic GP-33-specific CTLs (P14 cells) demonstrated that P14 cells lacking ST2 didn’t exhibit the breadth of effector function as control P14 cells, many of which co-expressed. IFN-γ, tumor necrosis factor (TNF)-α, IL-2, and the degranulation marker CD107a in various combinations. Rather, the vast majority of ST2-deficient P14 cells were monofunctional or completely lacked effector function, and failed to express markers of effector CTLs. In contrast, the development of LCMV-specific memory cell pools wasn’t affected by ST2 deficiency. “This supported the concept that inflammatory signals are more important for primary effector CTL responses than for memory formation,” the authors state.
The team finally determined that in the case of LCMV infection, it was nonhematopoietic cells in the spleen that were the source of IL-33. “In light of the evidence for IL-33 to act as an alarmin, our findings offer a new molecular link to understand how viral replication, commonly thought of as ‘danger’, can enhance CTL responses to infection,” they conclude. “PAMPs act primarily on professional antigen-presenting cells and thereby are decisive for efficient priming of CTLs. IL-33—and possibly also other alarmins—have complementary and nonredundant functions, and in the case of IL-33 act on antiviral CTLs directly. Taken together, this study establishes a paradigm for the role of nonhematopoietic cells providing alarmins to augment and differentiate protective CTL responses to viral infection.”
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