Act1 is a negative regulator in T and B cells via direct inhibition of STAT3

Cun-Jin Zhang, Chenhui Wang, Meiling Jiang, Chunfang Gu, Jianxin Xiao, Xing Chen, Bradley N. Martin, Fangqiang Tang, Erin Yamamoto, Yibo Xian, Han Wang, Fengling Li, R. Balfour Sartor, Howard Smith, M. Elaine Husni, Fu-Dong Shi, Ji Gao, Julie Carman, Ashok Dongre, Susan C. McKarns, Ken Coppieters, Trine N. Jørgensen, Warren J. Leonard and Xiaoxia Li ()
Additional contact information
Cun-Jin Zhang: Cleveland Clinic
Chenhui Wang: Cleveland Clinic
Meiling Jiang: Cleveland Clinic
Chunfang Gu: Cleveland Clinic
Jianxin Xiao: Cleveland Clinic
Xing Chen: Cleveland Clinic
Bradley N. Martin: Cleveland Clinic
Fangqiang Tang: Cleveland Clinic
Erin Yamamoto: Cleveland Clinic
Yibo Xian: Cleveland Clinic
Han Wang: Cleveland Clinic
Fengling Li: University of North Carolina
R. Balfour Sartor: University of North Carolina
Howard Smith: Cleveland Clinic
M. Elaine Husni: Cleveland Clinic
Fu-Dong Shi: Tianjin Medical University General Hospital
Ji Gao: Bristol-Myers Squibb
Julie Carman: Bristol-Myers Squibb
Ashok Dongre: Bristol-Myers Squibb
Susan C. McKarns: University of Missouri School of Medicine
Ken Coppieters: Novo Nordisk A/S
Trine N. Jørgensen: Cleveland Clinic
Warren J. Leonard: National Institutes of Health
Xiaoxia Li: Cleveland Clinic

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) deficient mice develop spontaneous SLE- and Sjögren’s-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1–STAT3 complex, deficiency of Act1 (but not Il17ra-, Il17rc-, or Il17rb) results in hyper IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjögren’s-like diseases in Act1−/− mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T–B cell interaction for B cell expansion and antibody production. Moreover, anti-IL-21 ameliorates the SLE- and Sjögren’s-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjögren’s-like syndrome in patients containing Act1 mutation.

Date: 2018
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DOI: 10.1038/s41467-018-04974-3

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