MAPK3 deficiency drives autoimmunity via DC arming.
DC are professional APC that instruct T cells during the inflammatory course of EAE. We have previously shown that MAPK3 (Erk1) is important for the induction of T-cell anergy. Our goal was to determine the influence of MAPK3 on the capacity of DC to arm T-cell responses in autoimmunity. We report that DC from Mapk3(-/-) mice have a significantly higher membrane expression of CD86 and MHC-II and--when loaded with the myelin oligodendrocyte glycoprotein--show a superior capacity to prime naïve T cells towards an inflammatory phenotype than Mapk3(+/+) DC. Nonetheless and as previously described, Mapk3(-/-) mice were only slightly but not significantly more susceptible to myelin oligodendrocyte glycoprotein-induced EAE than WT littermate mice. However, Mapk3(+/+) mice engrafted with Mapk3(-/-) BM (KO-->WT) developed a severe form of EAE, in direct contrast to WT-->KO mice, which were even less sick than control WT-->WT mice. An infiltration of DC and accumulation of Th17 cells was also observed in the CNS of KO-->WT mice. Therefore, triggering of MAPK3 in the periphery might be a therapeutic option for the treatment of neuroinflammation since absence of this kinase in the immune system leads to severe EAE.
Bendix
Ivo
I
Max Delbruck Center for Molecular Medicine, Berlin, Germany.
Pfueller
Caspar F
CF
Leuenberger
Tina
T
Glezeva
Nadezhda
N
Siffrin
Volker
V
Müller
Yasmin
Y
Prozorovski
Timour
T
Hansen
Wiebke
W
Schulze Topphoff
Ulf
U
Loddenkemper
Christoph
C
Zipp
Frauke
F
Waiczies
Sonia
S
D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D051940:B7-2 Antigen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology / Q000633:toxicity; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D011828:Radiation Chimera; D013047:Specific Pathogen-Free Organisms; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D063308:Myelin-Oligodendrocyte Glycoprotein; C111390:OVA 323-339; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D010047:Ovalbumin; D048052:Mitogen-Activated Protein Kinase 3