Basophil-associated OX40 Ligand Participates in the Initiation of Th2 Responses during Airway Inflammation

Di, Caixia; Lin, Xinhua; Zhang, Yanjie; Zhong, Wenxiang; Yuan, Yufan; Zhou, Tong; Liu, Junling; Xia, Zhenwei

doi:10.1074/jbc.m115.642637

Cited by 22 publications

(15 citation statements)

References 46 publications

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“…However, it remains unclear how antigen‐specific type 2 responses are initiated, given that Th2 cell polarization relies on IL‐4 and DCs, whereas naive DCs and CD4 + T cells do not produce IL‐4. Prior studies from us and others demonstrated that basophils play a role in modulating type 2 responses by producing IL‐4 after crosslinking with surface Fc receptor for IgE (FcεRI) and by acting as APCs to prime Th2 cell differentiation . Consistently, depleting TSLP or removing basophils abrogates airway inflammation in eosinophilic asthma , indicating their necessity for the pathogenesis of allergic asthma .…”

Section: Introductionmentioning

confidence: 90%

Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

et al. 2018

Eur J Immunol

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Epithelial cells (ECs)‐derived cytokines are induced by different stimuli through pattern recognition receptors (PRRs) to mount a type‐2‐cell‐mediated immune response; however, the underlying mechanisms are poorly characterized. Here, we demonstrated asthmatic features in both primary bronchial epithelial cells (pBECs) and mouse model using several allergens including ovalbumin (OVA), house dust mite (HDM), or Alternaria alternata. We found that toll‐like receptor 2 (TLR2) was highly induced in ECs but not dendritic cells (DCs) by various allergens, leading to recruitment of circulating basophils into the lung via C‐C chemokine ligand‐2 (CCL2). TLR2 expression increased thymic stromal lymphopoietin (TSLP) production through the NF‐κB and JNK signaling pathways to extend the survival of recruited basophils and resident DCs in the lung, predisposing a type‐2‐cell‐mediated airway inflammation. Conversely, TLR2 deficiency impaired http://secretion of TSLP and CCL2, decreased infiltration of lung basophils, and increased resistance to Th2 response. Blocking TSLP also phenocopied these phenomena. Our findings reveal a pro‐inflammatory role of airway ECs through a TLR2‐dependent TSLP production, which may have implication for treating allergic asthma.

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Section: Introductionmentioning

confidence: 90%

Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

et al. 2018

Eur J Immunol

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“…Studies in allergic airway hypersensitivity models in mice have demonstrated that OX40 ligation increases airway hyperreactivity, while OX40 blockade or deficiency was associated with a reduced Th2 cell response and decreased airway sensitivity in preclinical models (Di et al, 2015; Hong et al, 2015; Kaur and Brightling, 2012). Analysis of clinical biopsies demonstrate a corresponding increase in OX40 + T cells in the airways of mildly asthmatic patients (Siddiqui et al, 2010) and inflamed joints of rheumatoid arthritis patients (Gwyer Findlay et al, 2014), but infusion of a blocking anti-OX40L mAb did not improve hypersensitivity responses in a phase II clinical trial of mildly asthmatic patients (Gauvreau et al, 2014).…”

Section: The 1p36 Cosignaling Tnf Receptorsmentioning

confidence: 99%

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

et al. 2016

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Summary Cytokines related to Tumor Necrosis Factor (TNF) provide a communication network essential for coordinating multiple cell types into an effective host defense system against pathogens and malignant cells. The pathways controlled by the TNF superfamily differentiate both innate and adaptive immune cells as well as modulate stromal cells into microenvironments conducive to host defenses. Receptors in the TNFSF family activate diverse cellular functions, from production of type 1 interferons to the modulation of survival of antigen-activated T cells. Here, we focus attention on the subset of TNF superfamily receptors encoded on the immune response locus at Chr 1p36. Recent studies reveal diverse mechanisms utilized by these receptors to either co-stimulate or restrict immune responses. Translation of the fundamental mechanisms of the TNF superfamily is leading to the design of therapeutics that can alter pathogenic processes in several autoimmune diseases or promote immunity to tumors.

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“…It is found that in a mouse model of allergic asthma basophiles highly expressed OX40 ligand (OX40L) after activation. The results reveal a critical role of OX40L presented by the activated basophiles to initiate Th2 responses in an allergic asthma model, implicat-ing OX40-OX40L signaling as a potential therapeutic target in the treatment of allergic airway inflammation [12]. Blocking OX40-OX40L interaction has been considered an approach to the treatment of various diseases in which T cells play a critical role.…”

Section: Discussionmentioning

confidence: 94%

“…OX40L is expressed on activated antigen presenting cells like B cells [5], dendritic cells [6] and macrophages [7] as well as natural killer cells (NK cells) [8], Langerhans cells [9], airway smooth muscle cells [10] and vascular endothelial cells [11]. OX40L is also expressed on the surface of activated T cells which enhances further T cell responses [12]. Its receptor OX40 is expressed on activated T cells and its ligation to OX40L promotes pathways which regulate the T cell proliferation, effective activation, survival and cytokine release from the T cells [13].…”

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confidence: 99%

Ox40l Gene Polymorphism and Breast Cancer in Iranian Population

Monfared¹,

Mashayekhi²

2018

Exp. Onc.

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Background and Aim: The immune system plays an important role in the breast cancer development. OX40L (also known as TNFSF4), a membrane protein, which is a member of the tumor necrosis factor super family binds to its receptor OX40 and this co-stimulation has a crucial role in T cell proliferation, survival and cytokine release. Previous studies have shown that OX40L is associated with cancer. Due to the importance of the T cells in antitumor activities of OX40L we studied the association of rs3850641 (A→G) polymorphism of OX40L gene with the breast cancer. Materials and Methods: The study included 123 women with breast cancer and 126 healthy volunteers with no signs of cancer. Genomic DNA was extracted from blood leucocytes. Genotype and allele frequencies were determined in patients and control cases with the method of polymerase chain reaction-restriction fragment length polymorphism and the statistical analysis was performed by Med Calc. Results: The prevalence of genotype frequencies of AA/ AG/GG were 60.9%, 30.08% and 8.9% in patients with breast cancer cases and 74.6%, 18.25% and 7.14% in healthy volunteers while the A and G allelic frequency was 76.01 and 23.98% in patients and 83.73 and 16.26% in healthy controls, respectively. Statistical analysis has shown signiﬁcant difference from the comparison of genotype (p = 0.03). Conclusion: It is concluded that the rs3850641 SNP is significantly associated with the breast cancer susceptibility in Iranian population. However, further studies in larger populations including other genetic and environmental factors are required to achieve conclusion.

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Basophil-associated OX40 Ligand Participates in the Initiation of Th2 Responses during Airway Inflammation

Cited by 22 publications

References 46 publications

Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

Airway epithelial TSLP production of TLR2 drives type 2 immunity in allergic airway inflammation

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

Ox40l Gene Polymorphism and Breast Cancer in Iranian Population

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