Genetic deletion of Mst1 alters T cell function and protects against autoimmunity.
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.
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Konstantin V
KV
Salojin
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Brian D
BD
Hamman
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Wei Chun
WC
Chang
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Kanchan G
KG
Jhaver
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Amin
A
Al-Shami
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Jeannette
J
Crisostomo
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Carrie
C
Wilkins
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Ann Marie
AM
Digeorge-Foushee
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Jason
J
Allen
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Nita
N
Patel
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Suma
S
Gopinathan
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Julia
J
Zhou
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Amr
A
Nouraldeen
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Theodore C
TC
Jessop
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Jeffrey T
JT
Bagdanoff
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
David J
DJ
Augeri
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Robert
R
Read
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Peter
P
Vogel
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Jonathan
J
Swaffield
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Alan
A
Wilson
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Kenneth A
KA
Platt
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Kenneth G
KG
Carson
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Alan
A
Main
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Brian P
BP
Zambrowicz
Lexicon Pharmaceuticals, Inc, The Woodlands, Texas, United States of America.
Tamas
T
Oravecz
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015551:Autoimmunity; D001483:Base Sequence; D017931:DNA Primers; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor