PURPOSE OF THE STUDY.
Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas there is less known about how endogenous signals of tissue damage (known as alarmins) are involved in antiviral defenses.
Mice were infected with lymphocytic choriomeningitis virus (LCMV), a single-stranded RNA virus, and a genome-wide cDNA expression analysis of total spleen tissue was performed and compared with the uninfected mouse. From a large panel of interleukins and inflammatory cytokines, interferon-γ and interleukin (IL)-33 (along with its receptor ST2) were the most highly upregulated. Infection with LCMV, as well as a murine herpesvirus (MHV-68), was performed in wild-type mice, mice deficient in IL-33 (in IL-33−/−), and mice in which IL-33 effects were blocked with a soluble decoy receptor (Il1-rl1-Fc). Proliferative responses of cytotoxic lymphocytes (CTLs) specific for LCMV were measured.
Levels of IL-33 peaked at 3 to 5 days after infection, mirroring levels of LCMV mRNA. After infection with LCMV, proliferative responses of virus-specific CD8+ T cells were 90% lower in IL-33−/− mice and in mice with IL-33 decoy receptors, and CTL responses were absent. Productive viral replication was necessary for IL-33–mediated CTL proliferation. Additionally, recombinant IL-33 significantly augmented CTL responses to other viruses (vaccinia-based vectors), and CTLs appeared to respond to IL-33 directly. Last, the authors provided evidence that IL-33 expression was produced by fibroblastic reticular cells, a stromal cell population of the T-cell zone of the spleen and an important target of LCMV infection.
These findings suggest that the alarmin IL-33 provides a molecular link to understand how viral replication can enhance CTL responses to infection. IL-33 also serves as a signal from nonhematopoietic cells that acts directly on CTLs to augment protective responses.
IL-33 has attracted attention as a link between nonhematopoietic cells and the immune system. For example, it appears to be important in the developing airway as an inducer of a Th-2–dominated phenotype. This article shows a different role for IL-33 as an important inducer of CD8+ T cells in response to viral infection in the murine model. Children with asthma and other allergic diseases express higher levels of IL-33 and may thus have a stronger CTL-mediated response to viral infection.
- Copyright © 2012 by the American Academy of Pediatrics