Search

Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural properties and collectively determine tissue mechanics of lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive expansion upon immune challenge. We find that in murine models of immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that C-type lectin-like receptor 2 (CLEC-2)–podoplanin signaling regulates the cell surface mechanics of fibroblasts, providing a mechanically sensitive pathway to regulate lymph node remodeling. Perturbation of fibroblast mechanics through genetic deletion of podoplanin attenuates T cell activation. We find that increased tissue tension through the fibroblastic stromal meshwork is required to trigger the initiation of fibroblast proliferation and restore homeostatic cellular ratios and tissue structure through lymph node expansion.

Innate immune responses are important to protect the neonatal lung, which becomes exposed to commensal and pathogenic microorganisms immediately after birth, at a time when both the lung and the adaptive immune system are still developing. How immune cells in the neonatal lung respond to innate immune stimuli, including toll-like receptor (TLR) agonists, or viruses, is currently unclear. To address this, adult and neonatal mice were intranasally administered with various innate immune stimuli, respiratory syncytial virus (RSV) or influenza virus and cytokine and chemokine levels were quantified. The neonatal lungs responded weakly to RSV and most stimuli but more strongly than adult mice to R848 and influenza virus, both of which activate TLR7 and the inflammasome. Notably, neonatal lungs also contained higher levels of cAMP, a secondary messenger produced following adenosine receptor signaling, than adult lungs and increased responsiveness to R848 was observed in adult mice when adenosine was coadministered. Our data suggest that the neonatal lung may respond preferentially to stimuli that coactivate TLR7 and the inflammasome and that these responses may be amplified by extracellular adenosine. Improved understanding of regulation of immune responses in the neonatal lung can inform the development of vaccine adjuvants for the young.

Innate immune responses are important to protect the neonatal lung, which becomes exposed to commensal and pathogenic microorganisms immediately after birth, at a time when both the lung and the adaptive immune system are still developing. How immune cells in the neonatal lung respond to innate immune stimuli, including toll-like receptor (TLR) agonists, or viruses, is currently unclear. To address this, adult and neonatal mice were intranasally administered with various innate immune stimuli, respiratory syncytial virus (RSV) or influenza virus and cytokine and chemokine levels were quantified. The neonatal lungs responded weakly to RSV and most stimuli but more strongly than adult mice to R848 and influenza virus, both of which activate TLR7 and the inflammasome. Notably, neonatal lungs also contained higher levels of cAMP, a secondary messenger produced following adenosine receptor signaling, than adult lungs and increased responsiveness to R848 was observed in adult mice when adenosine was coadministered. Our data suggest that the neonatal lung may respond preferentially to stimuli that coactivate TLR7 and the inflammasome and that these responses may be amplified by extracellular adenosine. Improved understanding of regulation of immune responses in the neonatal lung can inform the development of vaccine adjuvants for the young.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections, especially in infants. Lung neutrophilia is a hallmark of RSV disease but the mechanism by which neutrophils are recruited and activated is unclear. Here, we investigate the innate immune signaling pathways underlying neutrophil recruitment and activation in RSV-infected mice. We show that MyD88/TRIF signaling is essential for lung neutrophil recruitment while MAVS signaling, leading to type I IFN production, is necessary for neutrophil activation. Consistent with that notion, administration of type I IFNs to the lungs of RSV-infected Mavs−/−mice partially activates lung neutrophils recruited via the MyD88/TRIF pathway. Conversely, lack of neutrophil recruitment to the lungs of RSV-infected Myd88/Trif−/−mice can be corrected by administration of chemoattractants and those neutrophils become fully activated. Interestingly, Myd88/Trif−/−mice did not have increased lung viral loads during RSV infection, suggesting that neutrophils are dispensable for viral control. Thus, two distinct pathogen sensing pathways collaborate for neutrophil recruitment and full activation during RSV infection.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections, especially in infants. Lung neutrophilia is a hallmark of RSV disease but the mechanism by which neutrophils are recruited and activated is unclear. Here, we investigate the innate immune signaling pathways underlying neutrophil recruitment and activation in RSV-infected mice. We show that MyD88/TRIF signaling is essential for lung neutrophil recruitment while MAVS signaling, leading to type I IFN production, is necessary for neutrophil activation. Consistent with that notion, administration of type I IFNs to the lungs of RSV-infected Mavs−/−mice partially activates lung neutrophils recruited via the MyD88/TRIF pathway. Conversely, lack of neutrophil recruitment to the lungs of RSV-infected Myd88/Trif−/−mice can be corrected by administration of chemoattractants and those neutrophils become fully activated. Interestingly, Myd88/Trif−/−mice did not have increased lung viral loads during RSV infection, suggesting that neutrophils are dispensable for viral control. Thus, two distinct pathogen sensing pathways collaborate for neutrophil recruitment and full activation during RSV infection.

Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections. Immunity to RSV is initiated upon detection of the virus by pattern recognition receptors, such as RIG-I-like receptors. RIG-I-like receptors signal via MAVS to induce the synthesis of proinflammatory mediators, including type I interferons (IFNs), which trigger and shape antiviral responses and protect cells from infection. Alveolar macrophages (AMs) are amongst the first cells to encounter invading viruses and the ones producing type I IFNs. However, it is unclear whether IFNs act to prevent AMs from serving as vehicles for viral replication. In this study, primary AMs from MAVS (Mavs-/-)- or type I IFN receptor (Ifnar1-/-)-deficient mice were exposed to RSV ex vivo. Wild-type (wt) AMs but not Mavs-/-and Ifnar1-/-AMs produced inflammatory mediators in response to RSV. Furthermore, Mavs-/-and Ifnar1-/-AMs accumulated more RSV proteins than wt AMs, but the infection was abortive. Thus, RIG-I-like receptor-MAVS and IFNAR signalling are important for the induction of proinflammatory mediators from AMs upon RSV infection, but this signalling is not central for controlling viral replication. The ability to restrict viral replication makes AMs ideal sensors of RSV infection and important initiators of immune responses in the lung.

Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)–coupled retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN–dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN–mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.

Lymphoid tissue returns to a steady state once each immune response is resolved, and although this occurs multiple times throughout life, its structural integrity and functionality remain unaffected. Stromal cells orchestrate cellular interactions within lymphoid tissue, and any changes to the microenvironment can have detrimental outcomes and drive disease. A breakdown in lymphoid tissue homeostasis can lead to a loss of tissue structure and function that can cause aberrant immune responses. This Review highlights recent advances in our understanding of lymphoid tissue function and remodelling in adaptive immunity and in disease states. We discuss the functional role of lymphoid tissue in disease progression and explore the changes to lymphoid tissue structure and function driven by infection, chronic inflammatory conditions and cancer. Understanding the role of lymphoid tissues in immune responses to a wide range of pathologies allows us to take a fuller systemic view of disease progression.

Lymph nodes (LNs) act as filters, constantly sampling peripheral cues. This is facilitated by the conduit network, a tubular structure of aligned extracellular matrix (ECM) fibrils ensheathed by fibroblastic reticular cells (FRCs). LNs undergo rapid 3- to 5-fold expansion during adaptive immune responses, but these ECM-rich structures are not permanently damaged. Whether conduit flow or filtering function is affected during LN expansion is unknown. Here, we show that conduits are partially disrupted during acute LN expansion, but FRC-FRC contacts remain connected. We reveal that polarized FRCs deposit ECM basolaterally using LL5-β and that ECM production is regulated at transcriptional and secretory levels by the C-type lectin CLEC-2, expressed by dendritic cells. Inflamed LNs maintain conduit size exclusion, and flow is disrupted but persists, indicating the robustness of this structure despite rapid tissue expansion. We show how dynamic communication between peripheral tissues and LNs provides a mechanism to prevent inflammation-induced fibrosis in lymphoid tissue.