Project description:Allergic asthma and obesity are the leading health problems in the world. Many studies have shown that obesity is a risk factor of development of asthma. However, the underlying mechanism has not been well established. In this study, we demonstrate that leptin, an adipokine elevated in obese individuals, promoted proliferation and survival of pro-allergic type 2 helper T cells and group 2 innate lymphoid cells and production of type 2 cytokines, which together contribute to allergic responses. Leptin activates mTORC1, MAPK, and STAT3 pathways in TH2 cells. The effects of leptin on TH2 cell proliferation, survival, and cytokine production are dependent on the mTORC1 and MAPK pathways as revealed by specific inhibitors. In vivo, leptin-deficiency led to attenuated experimental allergic airway inflammation. Our results thus support that obesity-associated elevation of leptin contributes to the increased susceptibility of asthma via modulation of pro-allergic lymphocyte responses.
Project description:Transcriptional profiling of mouse Th2, Th9, and iTreg cells. Transcriptomes were compared with that of naïve CD4 T cells. Goal was to screen subset-specific genes.
Project description:The differentiation of T cells along different lineages is central to the control of immunity. Here we have used a conditional gene knockout system to delete PKC lambda/iota selectively in activated T cells. With this system we have demonstrated that PKC lambda/iota is necessary for T-helper cell (Th2) cytokine production and optimal T-cell proliferation and allergic airway inflammation in vivo. Our data demonstrate that the activation of the transcription factors nuclear factor of activated T cells and NF-kappaB is impaired in PKC lambda/iota-deficient activated T cells. In addition, we present genetic knockout evidence in ex vivo experiments with primary T cells that PKC lambda/iota is critical for the control of cell polarity during T-cell activation. Therefore PKC lambda/iota emerges as a critical regulator of Th 2 activation.
Project description:The cytokines IL-4, IL-13, and thymic stromal lymphopoietin play a key role in allergic disease by virtue of their ability to initiate, maintain, and augment TH2 responses. These molecules mediate their effects through type 1 cytokine receptors, which bind cytokines with a characteristic structure. Receptors are expressed on a broad array of immune cell types and are integral to complex cytokine networks operating in health and disease. TH2-promoting cytokines bind different configurations of receptors. Receptor subunits can exist in surface-bound or soluble forms, as well as in isolation or in partnership with other subunits. Sharing of receptor subunits among different cytokine receptor complexes adds to the intricate landscape. This article describes the characteristics of receptors for IL-4, IL-13, and thymic stromal lymphopoietin and their respective ligands from a structure-function perspective. We detail the mechanisms of receptor complex assembly, the interrelated nature of these receptors, and the effect on allergic inflammation. The ability for novel and atypical types of receptors to modulate inflammatory processes is also discussed. We highlight current and emerging treatments that target TH2-promoting receptor complexes. Understanding the molecular features of these receptors provides insight into different disease phenotypes and the variable clinical outcomes arising from targeted therapies. These considerations can be used to inform future directions for research and creative strategies for treating individual patients.
Project description:BackgroundAssociations between vitamin D status and childhood asthma are increasingly reported, but direct causation and mechanisms underlying an effect remain unknown. We investigated the effect of early-life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD).MethodsIn utero and early-life vitamin D deficiency was achieved using a vitamin D-deficient diet for female mice during the third trimester of pregnancy and lactation. Offspring were weaned onto a vitamin D-deficient or vitamin D-replete diet, and exposure to intranasal house dust mite (HDM) or saline was commenced from day 3 of life for up to 6 weeks, when airway hyper-responsiveness (AHR), airway inflammation and remodelling were assessed.ResultsNeonatal mice that had in utero and early-life vitamin D deficiency had significantly increased pulmonary CD3(+) CD4(+) T1ST2(+) cells and reduced CD4(+) IL-10(+) cells. This effect was enhanced following HDM exposure. AHR in HDM-exposed mice was unaffected by vitamin D status. Introduction of vitamin D into the diet at weaning resulted in a significant reduction in serum IgE levels, reduced pulmonary eosinophilia and peri-bronchiolar collagen deposition.ConclusionPeri-natal vitamin D deficiency alone has immunomodulatory effects including Th2 skewing and reduced IL-10-secreting T regulatory cells, exaggerated with additional allergen exposure. Vitamin D deficiency in early life does not affect AHR, but contributes to disease severity with worse eosinophilic inflammation and airway remodelling. Importantly, supplementation with vitamin D improves both of these pathological abnormalities.
Project description:BACKGROUND: The role played by T helper cytokines under chronic, low grade inflammation as seen in type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) co-morbidity is less well studied. In the present study, we measured the serum levels of both Th1 and Th2 cytokines and correlated it with clinical risk factors for T2DM (Insulin Resistance (IR), Glycated haemoglobin (HbA1c)) and CAD (C-Reactive Protein (CRP), Intima Media Thickness (IMT) and Augmentation index (AGI)) in T2DM subjects with/without CAD. METHODOLOGY: The study subjects were recruited from Chennai Urban Rural Epidemiology Study (CURES). Serum cytokine profile was determined by multiplex cytokine assay in Control (n?=?61), T2DM (n?=?60), CAD (n?=?23) and T2DM-CAD (n?=?21) subjects. RESULTS: T2DM subjects showed a mixed Th1-Th2 profile. CAD subjects presented a Th1 profile with modest Th2 suppression while T2DM-CAD subjects showed enhanced Th1 profile with strong suppression of Th2 cytokines. Both Th1 and Th2 cytokines showed a positive correlation with FPG, HbA1c, hsCRP, IMT and AGI. Logistic regression analysis revealed a significant association of IL-12 (OR?=?9.3; 95% CI?=?3.2-70.7; p?=?0.016), IFN-? (OR?=?2.8; 95% CI?=?2.7-2.9, p?=?0.010), IL-4 (OR?=?2.7; 95% CI 2.7-2.7, p?=?0.010), IL-5 (OR?=?1.1; 95% CI?=?1.0-1.4; p?=?0.003) and IL-13 (OR?=?2; 95% CI?=?1.7-2.6; p?=?0.017) with T2DM-CAD. CONCLUSION: In conclusion, from the present study it appears that transition from T2DM or CAD to T2DM-CAD co-morbidity is associated with strong down regulation of Th2 cytokines and enhancement of Th1 responses.
Project description:Allergic airway inflammation is a disease in which T helper 2 (Th2) cells have a critical function. The molecular mechanisms controlling Th2 differentiation and function are of paramount importance in biology and immunology. Recently, a network of PB1-containing adapters and kinases has been shown to be essential in this process owing to its function in regulating cell polarity and the activation of critical transcription factors. Here, we show in vivo data showing that T-cell-specific NBR1-deficient mice show impaired lung inflammation and have defective Th2 differentiation ex vivo with alterations in T-cell polarity and the selective inhibition of Gata3 and nuclear factor of activated T c1 activation. These results establish NBR1 as a novel PB1 adapter in Th2 differentiation and asthma.
Project description:In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13. We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production. This T helper phenotype was accompanied by increased SOCS3 in the lung of Tyk-2 deficient asthmatic mice. Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung. These results suggest a role of Tyk-2 in different subsets of T helper cells mediated by SOCS3 regulation that is relevant for the treatment of asthma, cancer and autoimmune diseases.
Project description:BackgroundIL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, natural killer T cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined.ObjectiveWe sought to elucidate the role of TH9 cells in promoting mast cell accumulation in models of allergic lung inflammation.MethodsAdoptive transfer of ovalbumin-specific TH2 and TH9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild-type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation.ResultsAdoptive transfer experiments demonstrated that recipients of TH9 cells had significantly higher mast cell accumulation and expression of mast cell proteases compared with control or TH2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, a cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4(+) T cells, but not natural killer T cells or innate lymphoid cells, suggesting a TH cell-dependent phenotype. Rag1(-/-) mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable with accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment.ConclusionTH9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation.
Project description:PurposeThe etiology of meibomian gland dysfunction (MGD) is incompletely understood, despite being a common ophthalmic condition and an area of unmet medical need. It is characterized by an insufficiency in glandular provision of specialized lipids (meibum) to the tear film and is a major cause of dry eye. Work in the allergic eye disease (AED) mouse model has revealed an immunopathogenic role in MGD causation, now raising interest in the applicability of immunomodulatory therapies. As such, we herein ask whether inhibition of lymphocyte function associated antigen (LFA)-1/intracellular adhesion molecules (ICAM)-1 signaling via topical lifitegrast administration has a therapeutic effect on MGD in AED mice.MethodsMice were induced with AED by i.p. injection of ovalbumin (OVA) mixed with alum and pertussis toxin, followed 2 weeks later by once daily topical OVA challenges for 7 days. Mice were treated topically with 5% lifitegrast ophthalmic solution or vehicle (PBS) 30 min prior to challenge. We developed a clinical ranking method to assess MGD severity, and also scored clinical allergy. Conjunctivae and draining lymph nodes were collected for flow cytometry.ResultsTopical lifitegrast significantly inhibited clinical MGD severity, which was associated with diminished pathogenic TH17 cell and neutrophil numbers in the conjunctiva. No significant change in conjunctival TH2 cells or eosinophils, and only marginal differences in ocular allergy were observed.ConclusionsIn AED mice, lifitegrast inhibited MGD severity marked by a reduction in select immune populations in the conjunctiva. Our findings warrant future examination of lifitegrast in the treatment of patients with forms of MGD.