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; Xiaoxia Li

doi:10.1038/s41467-018-04974-3

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

Nat Commun. 2018 Jul 16;9(1):2745. doi: 10.1038/s41467-018-04974-3.

Authors

Cun-Jin Zhang^{1

2

3}, Chenhui Wang^{1

4

5}, Meiling Jiang^{1

6}, Chunfang Gu¹, Jianxin Xiao¹, Xing Chen¹, Bradley N Martin¹, Fangqiang Tang¹, Erin Yamamoto¹, Yibo Xian¹, Han Wang¹, Fengling Li⁷, R Balfour Sartor^{7

8}, Howard Smith⁹, M Elaine Husni⁹, Fu-Dong Shi^{2

3

10}, Ji Gao¹¹, Julie Carman¹¹, Ashok Dongre¹¹, Susan C McKarns^{12

13}, Ken Coppieters¹⁴, Trine N Jørgensen¹, Warren J Leonard¹⁵, Xiaoxia Li¹⁶

Affiliations

¹ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44106, USA.
² Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300051, China.
³ Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
⁴ Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
⁵ Wuhan Institute of Biotechnology, Wuhan, 430200, China.
⁶ Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
⁷ National Gnotobiotic Rodent Resource Center, Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁸ Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁹ Department of Rheumatologic and Immunologic Disease, Cleveland Clinic, Cleveland, OH, 44106, USA.
¹⁰ Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
¹¹ Discovery Biology, Bristol-Myers Squibb, Princeton, NJ, 08540, USA.
¹² Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
¹³ Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
¹⁴ Type 1 Diabetes Center, Novo Nordisk A/S, Søborg, 2860, Denmark.
¹⁵ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
¹⁶ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44106, USA. lix@ccf.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / deficiency
Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / immunology
Animals
Antibodies, Monoclonal / pharmacology
B-Lymphocytes / drug effects
B-Lymphocytes / immunology*
B-Lymphocytes / pathology
Cell Differentiation
Disease Models, Animal
Female
Gene Expression Regulation
Interleukin-17 / genetics
Interleukin-17 / immunology
Interleukins / antagonists & inhibitors
Interleukins / genetics*
Interleukins / immunology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / immunology
Leukocytes, Mononuclear / pathology
Lupus Erythematosus, Systemic / drug therapy
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / immunology
Lupus Erythematosus, Systemic / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Primary Cell Culture
Receptors, Interleukin / deficiency
Receptors, Interleukin / genetics
Receptors, Interleukin / immunology
Receptors, Interleukin-17 / deficiency
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / immunology
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / immunology
Signal Transduction
Sjogren's Syndrome / drug therapy
Sjogren's Syndrome / genetics*
Sjogren's Syndrome / immunology
Sjogren's Syndrome / pathology
Spleen
T-Lymphocytes / drug effects
T-Lymphocytes / immunology*
T-Lymphocytes / pathology

Substances

Adaptor Proteins, Signal Transducing
Antibodies, Monoclonal
Il17a protein, mouse
Il17ra protein, mouse
Il17rb protein, mouse
Il17rc protein, mouse
Interleukin-17
Interleukins
Receptors, Interleukin
Receptors, Interleukin-17
STAT3 Transcription Factor
Stat3 protein, mouse
Traf3ip2 protein, mouse
interleukin-23 receptor, mouse
interleukin-21

Abstract

Publication types

MeSH terms

Substances

Grants and funding