Neutrophils Recruited by IL-22 in Peripheral Tissues Function as TRAIL-Dependent Antiviral Effectors against MCMV

The small hydrophobic (SH) gene of respiratory syncytial virus (RSV), a major cause of infant hospitalization, encodes a viroporin of unknown function. SH gene knockout virus (RSV ⌬SH) is partially attenuated in vivo, but not in vitro, suggesting that the SH protein may have an immunomodulatory role. RSV ⌬SH has been tested as a live attenuated vaccine in humans and cattle, and here we demonstrate that it protected against viral rechallenge in mice. We compared the immune response to infection with RSV wild type and RSV ⌬SH in vivo using BALB/c mice and in vitro using epithelial cells, neutrophils, and macrophages. Strikingly, the interleukin-1␤ (IL-1␤) response to RSV ⌬SH infection was greater than to wild-type RSV, in spite of a decreased viral load, and when IL-1␤ was blocked in vivo, the viral load returned to wild-type levels. A significantly greater IL-1␤ response to RSV ⌬SH was also detected in vitro, with higher-magnitude responses in neutrophils and macrophages than in epithelial cells. Depleting macrophages (with clodronate liposome) and neutrophils (with anti-Ly6G/1A8) demonstrated the contribution of these cells to the IL-1␤ response in vivo, the first demonstration of neutrophilic IL-1␤ production in response to viral lung infection. In this study, we describe an increased IL-1␤ response to RSV ⌬SH, which may explain the attenuation in vivo and supports targeting the SH gene in live attenuated vaccines. IMPORTANCE There is a pressing need for a vaccine for respiratory syncytial virus (RSV). A number of live attenuated RSV vaccine strains have been developed in which the small hydrophobic (SH) gene has been deleted, even though the function of the SH protein is unknown. The structure of the SH protein has recently been solved, showing it is a pore-forming protein (viroporin). Here, we demonstrate that the IL-1␤ response to RSV ⌬SH is greater in spite of a lower viral load, which contributes to the attenuation in vivo. This potentially suggests a novel method by which viruses can evade the host response. As all Pneumovirinae and some Paramyxovirinae carry similar SH genes, this new understanding may also enable the development of live attenuated vaccines for both RSV and other members of the Paramyxoviridae. R espiratory syncytial virus (RSV) is the most significant cause of bronchiolitis and pneumonia in infants for which there is no vaccine (1). Recent advances in the understanding of the infant immune response to vaccination suggest that a live attenuated vaccine given in infancy may be the most effective approach to prevent RSV infection (2), potentially in combination with maternal immunization using recombinant F protein (3). This is supported by the successful introduction of live attenuated influenza vaccine to the childhood vaccination schedule (4) in conjunction with immunization during pregnancy with the trivalent inactivated vaccine (5). One issue with live attenuated RSV vaccines has been balancing immunogenicity and safety (6). Two approaches are used to develop live attenuated v...

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.

CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the β-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that β-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.