Deletion of IL-4Rα signaling on B cells limits hyperresponsiveness depending on antigen load

Hadebe, Sabelo; Khumalo, Jermaine; Mangali, Sandisiwe; Mthembu, Nontobeko; Ndlovu, Hlumani; Scibiorek, Martyna; Ngomti, Amkele; Kirstein, Frank; Brombacher, Frank

doi:10.1016/j.jaci.2020.12.635

Cited by 10 publications

(12 citation statements)

References 49 publications

(119 reference statements)

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“…In vitro studies first showed that Th2 cells (or IL-4) could polarize B cells to produce IL-4, which in turn, amplified Th2 responses ( 5 , 17 ). Subsequently, it was shown that IL-4-responsive B cells are important for Th2 polarization, and promoted clearance of helminthic infections, while worsening asthma and leishmaniasis ( 20 , 21 ). However, the in vivo role of B cell IL-4 per se was unclear, with studies showing that it was required for Th2 responses with resultant worsening of leishmaniasis, but it was not required for Th2 responses and protection from helminthic infections or pulmonary/airway inflammation in allergic asthma ( 7 , 20 – 22 ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the role of B cell IL-4 in promoting Th2 responses modulating disease in vivo , remains uncertain. Constitutive B cell-specific deletion of IL-4Rα reduced Th2 and increased Th1 responses, enhancing susceptibility to Schistosoma mansoni (controlled by Type 2 responses), while reducing Th2-driven cutaneous Leishmania major infection and house dust mite (HDM)-induced asthma ( 20 , 21 ). These studies establish a clear role for IL-4-responsive B cells in vivo .…”

Section: Introductionmentioning

confidence: 99%

“…In a bone marrow chimera model, loss of B cell IL-4 expression reduced Th2 and augmented Th1 responses, conferring protection to cutaneous L. major ( 20 ). However, in HDM-induced asthma, transfer of IL-4/IL-13 −/− B cells into μMT mice reduced airway hyperresponsiveness but had no effect on the Th2 response or airway inflammation—suggesting that IL-4 responsiveness, rather than IL-4 production by B cells, drives Th2 responses and airway inflammation ( 21 ). In agreement, while IL-4-responsive B cells are required, B cell IL-2 and not IL-4, drove protective Th2 responses to H. polgyrus infection ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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B Cell IL-4 Drives Th2 Responses In Vivo, Ameliorates Allograft Rejection, and Promotes Allergic Airway Disease

et al. 2022

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B cells can be polarized to express various cytokines. The roles of IFNγ and IL-10, expressed respectively by B effector 1 (Be1) and Bregs, have been established in pathogen clearance, tumor growth, autoimmunity and allograft rejection. However, the in vivo role of B cell IL-4, produced by Be2 cells, remains to be established. We developed B-IL-4/13 iKO mice carrying a tamoxifen-inducible B cell-specific deletion of IL-4 and IL-13. After alloimmunization, B-IL-4/13 iKO mice exhibited decreased IL-4+ Th2 cells and IL-10+ Bregs without impact on Th1, Tregs, or CD8 T cell responses. B-IL-4/13 iKO mice rejected islet allografts more rapidly, even when treated with tolerogenic anti-TIM-1 mAb. In ovalbumin-induced allergic airway disease (AAD), B-IL-4/13 iKO mice had reduced inflammatory cells in BAL, and preserved lung histology with markedly decreased infiltration by IL-4+ and IL-5+ CD4+ T cells. Hence, B cell IL-4 is a major driver of Th2 responses in vivo which promotes allograft survival, and conversely, worsens AAD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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B Cell IL-4 Drives Th2 Responses In Vivo, Ameliorates Allograft Rejection, and Promotes Allergic Airway Disease

et al. 2022

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“…These results suggested that IL-4 signaling was indispensable for maintaining Treg cells inhibitory function. Notably, it was Treg cell specific- ( 23 , 26 ), but not systemic ( 27 ) or other types of immune cell specific- IL-4 signaling ( 28 , 29 ) deletion that led to more serious immune inflammatory response, emphasizing the particular promotion by IL-4 signaling on Treg cell immunosuppressive function. The underlying mechanisms causing this discrepancy are worth exploring.…”

Section: The Promotions Of Treg Functions By Effector Th Cell Mechanismsmentioning

confidence: 99%

The Mechanisms of Effector Th Cell Responses Contribute to Treg Cell Function: New Insights into Pathogenesis and Therapy of Asthma

et al. 2022

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CD4 + helper T (Th) cell subsets are critically involved in the pathogenesis of asthma. Naive Th cells differentiate into different subsets under the stimulation of different sets of cytokines, and the differentiation process is dominantly driven by lineage specific transcription factors, such as T-bet (Th1), GATA3 (Th2), RORγt (Th17) and Foxp3 (Treg). The differentiation mechanisms driven by these transcription factors are mutually exclusive, resulting in functional inhibition of these Th subsets to each other, particularly prominent between effector Th cells and Treg cells, such as Th2 versus Treg cells and Th17 versus Treg cells. Being of significance in maintaining immune homeostasis, the balance between effector Th cell response and Treg cell immunosuppression provides an immunological theoretical basis for us to understand the immunopathological mechanism and develop the therapy strategies of asthma. However, recent studies have found that certain factors involved in effector Th cells response, such as cytokines and master transcription factors (IL-12 and T-bet of Th1, IL-4 and GATA3 of Th2, IL-6 and RORγt of Th17), not only contribute to immune response of effector Th cells, but also promote the development and function of Treg cells, therefore bridging the interplay between effector Th cell immune responses and Treg cell immunosuppression. Although we have an abundant knowledge concerning the role of these cytokines and transcription factors in effector Th cell responses, our understanding on their role in Treg cell development and function is scattered thus need to be summarized. This review summarized the role of these cytokines and transcription factors involved in effector Th cell responses in the development and function of Treg cells, in the hope of providing new insights of understanding the immunopathological mechanism and seeking potential therapy strategies of asthma.

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“…A high dose and a low dose treatment schedule were used to induce symptoms of allergic asthma in mice (31). Mice were anaesthetised with ketamine (Anaket-V;…”

Section: House Dust-mite Induced Allergic Airway Diseasementioning

confidence: 99%

IgM regulates airway hyperresponsiveness via modulation of actin associated genes.

Hadebe

Savulescu

Khumalo³

et al. 2021

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Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model by sensitising wild type (WT) and IgM-deficient (IgM-/-) mice with HDM. We validated our findings using CRISPR and single cell force cytometry in human ASM. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and erythroid differentiation regulator 1 (Erdr1). Deletion of BAIAP2L1 and ERDR1 reduced human ASM contraction when stimulated with TNF-α. These are unprecedented findings and have implications in future treatment of asthma beyond current therapies.

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Deletion of IL-4Rα signaling on B cells limits hyperresponsiveness depending on antigen load

Cited by 10 publications

References 49 publications

B Cell IL-4 Drives Th2 Responses In Vivo, Ameliorates Allograft Rejection, and Promotes Allergic Airway Disease

B Cell IL-4 Drives Th2 Responses In Vivo, Ameliorates Allograft Rejection, and Promotes Allergic Airway Disease

The Mechanisms of Effector Th Cell Responses Contribute to Treg Cell Function: New Insights into Pathogenesis and Therapy of Asthma

IgM regulates airway hyperresponsiveness via modulation of actin associated genes.

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