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The pleiotropic cytokine IL-6 plays an integral role not only in innate inflammatory responses but also in the activation and differentiation of lymphocyte subsets. In this study, by using a conditional knockout (cKO) model with selective IL-6 receptor deletion in T cells (IL-6R-cKO), we demonstrated that T cell-specific IL-6R signaling is essential for viral control during persistent lymphocytic choriomeningitis virus clone 13 infection. Strikingly, we observed that in contrast to previous studies with ubiquitous IL-6 deletion or blockade, specific IL-6R deletion in T cells did not affect T follicular helper (Tfh) cell accumulation unless IL-6R-deficient T cells were competing with wild-type cells in mixed bone marrow chimeras. In contrast, Tfh cells from IL-6R-cKO-infected mice exhibited reduced ICOS expression in both chimeric and nonchimeric settings, and this sole identifiable Tfh defect was associated with reduced germinal centers, compromised Ig switch and low avidity of lymphocytic choriomeningitis virus-specific Abs despite intact IL-6R expression in B cells. We posit that IL-6R cis-signaling is absolutely required for appropriate ICOS expression in Tfh cells and provides a competitive advantage for Tfh accumulation, enabling generation of optimal B cell and Ab responses, and ultimately viral control during in vivo chronic infection.

Chronic viral infections represent a major challenge to the host immune response, and a unique network of immunological elements, including cytokines, are required for their containment. By using a model persistent infection with the natural murine pathogen lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) we investigated the role of one such cytokine, interleukin-27 (IL-27), in the control of chronic infection. We found that IL-27 receptor (IL-27R) signaling promoted control of LCMV Cl13 as early as days 1 and 5 after infection and that il27p28 transcripts were rapidly elevated in multiple subsets of dendritic cells (DCs) and myeloid cells. In particular, plasmacytoid DCs (pDCs), the most potent type 1 interferon (IFN-I)-producing cells, significantly increased il27p28 in a Toll-like receptor 7 (TLR7)-dependent fashion. Notably, mice deficient in an IL-27-specific receptor, WSX-1, exhibited a pleiotropy of innate and adaptive immune alterations after chronic lymphocytic choriomeningitis virus (LCMV) infection, including compromised NK cell cytotoxicity and antibody responses. While, the majority of these immune alterations appeared to be cell extrinsic, cell-intrinsic IL-27R was necessary to maintain early pDC numbers, which, alongside lower IFN-I transcription in CD11b+ DCs and myeloid cells, may explain the compromised IFN-I elevation that we observed early after LCMV Cl13 infection in IL-27R-deficient mice. Together, these data highlight the critical role of IL-27 in enabling optimal antiviral immunity early and late after infection with a systemic persistent virus and suggest that a previously unrecognized positive-feedback loop mediated by IL-27 in pDCs might be involved in this process.IMPORTANCE Persistently replicating pathogens, such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, represent major health problems worldwide. These infections impose a long-term challenge on the host immune system, which must be heavily and continuously regulated to keep pathogen replication in check without causing fatal immunopathology. Using a persistently replicating rodent pathogen, LCMV, in its natural host, we identified the cellular sources and effects of one important regulatory pathway, interleukin-27 receptor WSX-1 signaling, that is required for both very early and late restriction of chronic (but not acute) infection. We found that WSX-1 was necessary to promote innate immunity and the development of aberrant adaptive immune responses. This not only highlights the role of IL-27 receptor signaling in regulating distinct host responses that are known to be necessary to control chronic infections, but also positions IL-27 as a potential therapeutic target for their modulation.

Background: Preschool wheeze attacks triggered by recurrent viral infections, including respiratory syncytial virus (RSV), are associated with an increased risk of childhood asthma. However, mechanisms that lead to asthma following early‐life viral wheezing remain uncertain. Methods: To investigate a causal relationship between early‐life RSV infections and onset of type 2 immunity, we developed a neonatal murine model of recurrent RSV infection, in vivo and in silico, and evaluated the dynamical changes of altered airway barrier function and downstream immune responses, including eosinophilia, mucus secretion and type 2 immunity. Results: RSV infection of neonatal BALB/c mice at 5 and 15 days of age induced robust airway eosinophilia, increased pulmonary CD4+IL‐13+ and CD4+IL‐5+ cells, elevated levels of IL‐13 and IL‐5 and increased airway mucus at 20 days of age. Increased bronchoalveolar lavage albumin levels, suggesting epithelial barrier damage, were present and persisted following the second RSV infection. Computational in silico simulations demonstrated that recurrent RSV infection resulted in severe damage of the airway barrier (epithelium), triggering the onset of type 2 immunity. The in silico results also demonstrated that recurrent infection is not always necessary for the development of type 2 immunity, which could also be triggered with single infection of high viral load or when the epithelial barrier repair is compromised. Conclusions: The neonatal murine model demonstrated that recurrent RSV infection in early life alters airway barrier function and promotes type 2 immunity. A causal relationship between airway barrier function and type 2 immunity was suggested using in silico model simulations. [ABSTRACT FROM AUTHOR]

Background: Allergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (TFH) are crucial in T‐dependent B‐cell responses and have been implicated in allergic airway disease (AAD). TFH, unlike other CD4+ T cells, are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T‐cell priming; therefore, disrupting this signal can impair TFH responses. However, the contribution of TFH to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells have not been evaluated. Methods: To establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of TFH on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS Ligand‐targeted antibodies, three times a week for the last 2 weeks. Results: TFH were first observed in the lung‐draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH but did not affect the differentiation of other CD4+ T‐cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness. Conclusions: TFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma. Chronic allergen exposure drives T follicular helper cell (TFH) formation in the lung draining lymph node after 1 week and the lung tissue after 3 weeks TFH at both sites interact with germinal centre B cells and are critical for the production of allergen specific IgE Allergic disease is also hallmarked by cellular inflammation and airway hyperresponsiveness driven by IL‐13 Blocking ICOS and ICOS‐L interactions between TFH and B cells reduces allergen specific IgE production and also dampens other hallmark symptoms of allergic airway disease [ABSTRACT FROM AUTHOR]