한빛사논문
- 조회717
Jee H. Lee PhDa,b,∗, Le Zou Bsca,c, Runqing Yang Bscc, Jihye Han PhDa, Qingqing Wan Bsca,c, Xian Zhang Bscc, Sarah El Baghdady Bsca, Andrea Romana, Chris Elly Bsca, Hyung-seung Jin PhDa,d, Yoon Park PhDa,e, Michael Croft PhDb, Yun-Cai Liu PhDa,c,*
aDivision of Cell Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
bDivision of Immune Regulation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
cInstitute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
dDepartment of Convergence Medicine, ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
eCenter for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
JHL and LZ contributed equally
*Corresponding author
Abstract
Background
Type 2 immunity can be modulated by regulatory T cell (Treg) activity. It has been suggested that the deubiquitinase CYLD plays a role in the development or function of Treg cells implying 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 function and T helper type (Th2) immune responses under steady state conditions and during helminth infection.
Methods
Foxp3-restricted CYLD conditional knockout mice (cKO) were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry and qPCR to understand how a lack of CYLD affected cytokine production, homing and suppression in Tregs. Target genes regulated by CYLD were identified and validated by microarray analysis, co-immunoprecipitation, shRNA knockdown, and transfection assays.
Results
Treg-specific CYLD knockout mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of interleukin-4 (IL-4) and failed to suppress allergen-induced lung inflammation. Supporting this, the cKO mice displayed enhanced protection against N. brasiliensis infection by contributing to type 2 immunity. Treg conversion into IL-4 producing cells was due to augmented MAPK and NF-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 MEK/ERK. 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 conversion into Th2-like effector cells, which potentiates parasite resistance.
논문정보
- Research article
- 2020년 12월 (BRIC 등록일 2020-12-15)
- 국내+국외 연구진
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