Lee, J.H. Zou, L. Yang, R. Han, J. Wan, Q. Zhang, X. El, Baghdady S. Roman, A. Elly, C. Jin, H.-S. Park, Yoon Croft, M. Liu, Y.-C. 2024-01-19T14:31:08Z 2024-01-19T14:31:08Z 2021-09-02 2021-07 0091-6749 https://pubs.kist.re.kr/handle/201004/116835 Background: Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent. Objective: We sought to investigate the role of CYLD in Treg cell function and TH2 cell immune responses under steady-state conditions and during helminth infection. Methods: Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays. Results: Treg cell？specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4？producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation. Conclusions: Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into TH2 cell？like effector cells, which potentiates parasite resistance. ？ 2020 American Academy of Allergy, Asthma & Immunology English Mosby Inc. The deubiquitinase CYLD controls protective immunity against helminth infection by regulation of Treg cell plasticity Article 10.1016/j.jaci.2020.10.042 1 Journal of Allergy and Clinical Immunology, v.148, no.1, pp.209 - 224.e9 Journal of Allergy and Clinical Immunology 148 1 209 224.e9 N scie scopus 000669908500003 2-s2.0-85099161249 Allergy Immunology Allergy Immunology Article T-CELLS TYPE-2 IMMUNITY TH2 CELLS ACTIVATION EXPRESSION PROMOTES IL-4 DIFFERENTIATION ENTEROPATHY HOMEOSTASIS CYLD deubiquitinase Helminth infection lung inflammation MAPK signaling NF-κB signaling Scinderin Treg cells type 2 immunity