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Our barrier surfaces are fundamental in protecting us from the outside world and segregating key biological processes. The immunological fortifications found at these sites therefore possess many distinct qualities, which are discussed in Immunology's series of reviews on Barrier Immunity. Together these reviews showcase novel biological processes identified through the use of state-of-the-art technologies, and specifically highlight how these change throughout our lives., (© 2020 The Authors. Immunology published by John Wiley & Sons Ltd.)

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.

Immune responses in early life are characterized by a failure to robustly generate long-lasting protective responses against many common pathogens or upon vaccination. This is associated with a reduced ability to generate T-cell dependent high affinity antibodies. This review highlights the differences in T-cell dependent antibody responses observed between infants and adults, in particular focussing on the alterations in immune cell function that lead to reduced T follicular helper cell-B cell crosstalk within germinal centres in early life. Understanding the distinct functional characteristics of early life humoral immunity, and how these are regulated, will be critical in guiding age-appropriate immunological interventions in the very young. [ABSTRACT FROM AUTHOR]

Immunity in the human respiratory tract is provided by a diverse range of tissue-resident cells, including specialized epithelial and macrophage populations and a network of innate and innate-like lymphocytes, such as natural killer cells, innate lymphoid cells, and invariant T cells. Lung-resident memory T and B cells contribute to this network following initial exposure to antigenic stimuli. This review explores how advances in the study of human immunology have shaped our understanding of this resident immune network and its response to two of the most commonly encountered inflammatory stimuli in the airways: viruses and allergens. It discusses the many ways in which pathogenic infection and allergic inflammation mirror each other, highlighting the key checkpoints at which they diverge and how this can result in a lifetime of allergic exacerbation versus protective anti-viral immunity. This review examines many ways in which pathogenic infection and allergic inflammation mirror each other, highlighting the key checkpoints at which they diverge and how this can result in a lifetime of allergic exacerbation versus protective anti-viral immunity. [ABSTRACT FROM AUTHOR]

Respiratory infections are a major cause of mortality and morbidity in very early life, and the immunity that results from them can often be weaker and less long lived than is seen in adults. Despite this our understanding of the immune system is largely derived from the study of adults, and a more age dependent focus is clearly required. This is particularly evident with respiratory syncytial virus, a leading cause of mortality in infants, and a pathogen which children are frequently re-infected with throughout early childhood, and thus a great concern to parents. Using murine models of RSV infection we have shown the cytokine signaling results in distinct outcomes in early life compared to adulthood. Most recently we have shown that IFN-g and IL-2, cytokines traditional linked to anti-viral T cell responses, act to curb virus specific antibody responses in early life allowing more severe re-infection. Abundant IL-2 production in neonates in particular blocks the formation of T-follicular helper cell dependent B cell responses, and modulating IL-2 signalling can be used to promote protective immunity. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes bronchiolitis, the main cause of infantile hospitalization. Immunity against reinfection is poor, and there is great interest in boosting vaccine responses using live vectors expressing host cytokines. We therefore constructed a recombinant RSV expressing murine interleukin 18 (RSV/IL-18), a cytokine capable of inducing strong antiviral immune responses. In vitro RSV/IL-18 replicated at wild-type levels and produced soluble IL-18. In naïve BALB/c mice, RSV/IL-18 infection significantly increased both IL-18 mRNA and protein and attenuated the peak viral load 3-fold. Despite a reduced viral load, RSV/IL-18 infection caused a biphasic weight loss at days 2 and 6 postinfection that was not seen in wild-type infection. Day 2 disease was associated with enhanced pulmonary natural killer (NK) cell numbers and activity and was prevented by NK cell depletion during infection; day 6 disease was correlated with CD8 T-cell recruitment and was enhanced by NK cell depletion. IL-18 expression during priming also enhanced RSV-specific antibody responses and T-cell responses on secondary RSV infection. Therefore, while IL-18 boosted antiviral immunity and reduced the viral load, its coexpression worsened disease. This is the first recombinant RSV with this property, and these are the first studies to demonstrate that NK cells can induce pathology during pulmonary viral infections. [ABSTRACT FROM AUTHOR]