Open AccessGenetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity
Author(s) -
Konstantin V. Salojin,
Brian D. Hamman,
Wei Chun Chang,
Kanchan Jhaver,
Amin Al-Shami,
Jeannette Crisostomo,
Carrie Wilkins,
Ann Marie Digeorge-Foushee,
Jason Allen,
Nita Patel,
Suma Gopinathan,
Julia Zhou,
Amr Nouraldeen,
Theodore C. Jessop,
Jeffrey T. Bagdanoff,
David J. Augeri,
Robert W. Read,
Peter Vogel,
Jonathan C. Swaffield,
Alan G. E. Wilson,
Kenneth A. Platt,
Kenneth G. Carson,
Alan J. Main,
Brian Zambrowicz,
Tamás Oravecz
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0098151
Subject(s) - autoimmunity , immune system , biology , experimental autoimmune encephalomyelitis , t cell , cytokine , microbiology and biotechnology , immunology , cancer research
Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4 + T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1 −/− B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1 −/− CD4 + T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4 + T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.