The molecular mechanisms that drive mucosal T helper type 2 (T(H)2) responses against parasitic helminths and allergens remain unclear. In this study, we demonstrate in mice that TFF2 (trefoil factor ...2), an epithelial cell-derived repair molecule, is needed for the control of lung injury caused by the hookworm parasite Nippostrongylus brasiliensis and for type 2 immunity after infection. TFF2 is also necessary for the rapid production of IL-33, a T(H)2-promoting cytokine, by lung epithelia, alveolar macrophages, and inflammatory dendritic cells in infected mice. TFF2 also increases the severity of allergic lung disease caused by house dust mite antigens or IL-13. Moreover, TFF2 messenger RNA expression is significantly increased in nasal mucosal brushings during asthma exacerbations in children. These experiments extend the biological functions of TFF2 from tissue repair to the initiation and maintenance of mucosal T(H)2 responses.
Studies examining the role of PD‐1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD‐1/PD‐L1 has distinct ...influences on different CD4+ T‐cell subsets. PD‐1/PD‐L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2‐type immune response, but by allowing the development of a concomitant Th17‐type immune response. Supporting differential CD4+ T‐cell responsiveness to PD‐1‐mediated inhibition, naïve PD‐1−/− mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD‐1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD‐1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4+ T‐cell subsets respond differentially to PD‐1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD‐1 family members. As the PD‐1/PD‐L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD‐1/PD‐L1 regulatory axis in some individuals.
Converging evidence supports neuroimmune factors in depression psychopathology. We previously reported reduced depression-like behavior in immunomodulatory G-protein-coupled receptor, T cell ...death-associated gene-8 (TDAG8) deficient mice. Here, we expand on those findings by investigating depression- and anxiety-associated behaviors, and cytokine profiles in TDAG8-deficient mice. TDAG8-deficiency reduced depression- and anxiety-associated behaviors in the forced swim test (FST), open-field test and elevated zero maze. Interestingly, cytokine expression, particularly IL-6, was attenuated within hippocampus and spleen in TDAG8-deficient mice following the FST. There were no differences in immune-cell frequencies. Collectively, these data suggest a contributory role of TDAG8 in neuroimmune regulation and depression-associated physiology.
•TDAG8-deficient mice show attenuated depression-like and anxiety-like behavior.•TDAG8−/− mice had attenuated post-stress interleukin-6 (IL-6) in hippocampus.•Reduced basal IL-6 expression in spleen was observed in TDAG8−/− mice.•TDAG8 receptor regulates neuroimmune homeostasis and depression-associated behaviors.
Rationale Workplace exposure to Trimellitic Anhydride (TMA), can elicit either an irritant response caused by free TMA or an IgE-mediated immune response which can occur when TMA binds to endogenous ...proteins like human serum albumin (HSA) and in susceptible individuals results in sensitization and potentially occupational asthma.
The role of natural CD4+CD25+ regulatory T (T reg) cells in the control of allergic asthma remains poorly understood. We explore the impact of T reg cell depletion on the allergic response in mice ...susceptible (A/J) or comparatively resistant (C3H) to the development of allergen-induced airway hyperresponsiveness (AHR). In C3H mice, anti-CD25-mediated T reg cell depletion before house dust mite treatment increased several features of the allergic diathesis (AHR, eosinophilia, and IgE), which was concomitant with elevated T helper type 2 (Th2) cytokine production. In similarly T reg cell-depleted A/J mice, we observed a moderate increase in airway eosinophilia but no effects on AHR, IgE levels, or Th2 cytokine synthesis. As our experiments suggested that T reg cell depletion in C3H mice before sensitization was sufficient to enhance the allergic phenotype, we characterized dendritic cells (DCs) in T reg cell-depleted C3H mice. T reg cell-depleted mice had increased numbers of pulmonary myeloid DCs with elevated expression of major histocompatibility complex class II, CD80, and CD86. Moreover, DCs from T reg cell-depleted mice demonstrated an increased capacity to stimulate T cell proliferation and Th2 cytokine production, which was concomitant with reduced IL-12 expression. These data suggest that resistance to allergen-driven AHR is mediated in part by CD4+CD25+ T reg cell suppression of DC activation and that the absence of this regulatory pathway contributes to susceptibility.
Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report ...evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.
Summary
Background
Recent studies have demonstrated that Th2 responses have the ability to antagonize Th17 responses. In mouse models of allergic asthma, blockade of Th2‐effector cytokines results in ...elaboration of Th17 responses and associated increases in pulmonary neutrophilia. While these can be controlled by simultaneous blockade of Th17‐associated effector cytokines, clinical trials of anti‐IL‐17/IL‐17RA blocking therapies have demonstrated increased of risk of bacterial and fungal infections. Identification of minimally effective doses of cytokine‐blocking therapies with the goal of reducing the potential emergence of infection‐related complications is a translationally relevant goal.
Objective
In the current report, we examine whether combined blockade of IL‐13 and IL‐17A, at individually sub‐therapeutic levels, can limit the development of allergic asthma while sparing expression of IL‐17A‐associated anti‐microbial effectors.
Methods
House dust mite was given intratracheally to A/J mice. Anti‐IL‐13 and anti‐IL‐17A antibodies were administered individually, or concomitantly at sub‐therapeutic doses. Airway hyper‐reactivity, lung inflammation, magnitude of Th2‐ and Th17‐associated cytokine production and expression of IL‐13‐ and IL‐17A‐induced genes in the lungs was assessed.
Results
Initial dosing studies identified sub‐therapeutic levels of IL‐13 and IL‐17A blocking mAbs that have a limited effect on asthma parameters and do not impair responses to microbial products or infection. Subsequent studies demonstrated that combined sub‐therapeutic dosing with IL‐13 and IL‐17A blocking mAbs resulted in significant improvement in airway hyperresponsiveness (AHR) and expression of IL‐13‐induced gene expression. Importantly, these doses neither exacerbated nor inhibited production of Th17‐associated cytokines, or IL‐17A‐associated gene expression.
Conclusion
This study suggests that combining blockade of individual Th2 and Th17 effector cytokines, even at individually sub‐therapeutic levels, may be sufficient to limit disease development while preserving important anti‐microbial pathways. Such a strategy may therefore have reduced potential for adverse events associated with blockade of these pathways.
The division of labor between pulmonary phagocytic subsets macrophage/monocyte and dendritic cell (DC) subpopulations has been described at the functional level. However, whether these lung ...phagocytes also display unique spatial distribution remains unclear. Here, to analyze cellular distribution in lung compartments and contacts between phagocyte subpopulations, we established an immunohistochemistry (IHC)-based method to clearly identify murine lung phagocyte subsets
based on differential expression of CD11c, CD11b, MHC-II, Langerin and mPDCA-1. Furthermore, we investigated subset-specific functional differences in antigen uptake and spatial changes upon allergic sensitization. Our staining allowed the distinction between alveolar macrophages (AMs), interstitial macrophage (IM) subpopulations, CD11b
DC subpopulations, CD103
DCs, and plasmacytoid DCs (pDCs). We identified interstitial regions between airways and around airways as regions of IM/CD11b
DC/CD103
DC clusters, where a subset of IMs (IM2) and CD103
DCs formed intense contacts that decreased upon allergic sensitization. These data indicate functional interactions between both cell types either in steady state or after antigen encounter affecting the development of allergies or tolerance. Furthermore, we observed major antigen uptake in AMs and IMs rather than DC subpopulations that was not restricted to airways and adjacent areas. This will enable to focus future studies to immunologically relevant cellular interactions and to unravel which cells are tipping the balance between pro-inflammatory immune responses or tolerance.
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which leads to elevated levels of pro-inflammatory mediators and microbial products in the amniotic fluid, which ...come in contact with fetal lungs. Yet, fetal pulmonary immune responses to such exposure remain poorly characterized. To address this gap, we used our established HCA model, in which pregnant Rhesus macaques receive intraamniotic (IA) saline or LPS. IA LPS induced a potent and rapid myeloid cell response in fetal lungs, dominated by neutrophils and monocytes/macrophages. Infiltrating and resident myeloid cells exhibited transcriptional profiles consistent with exposure to TLR ligands, as well as cytokines, notably IL-1 and TNFα. Although simultaneous, in vivo blockade of IL-1 and TNFα signaling did not prevent the inflammatory cell recruitment, it blunted the lung overall inflammatory state reducing communication between, and activation of, infiltrating immune cells. Our data indicate that the fetal innate immune system can mount a rapid multi-faceted pulmonary immune response to in utero exposure to inflammation. These data provide mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlight therapeutic potential of inflammatory blockade in the fetus.
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