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Brüstle, A.* ; Brenner, D.* ; Knobbe, C.B.* ; Lang, P.A.* ; Virtanen, C.* ; Hershenfield, B.M.* ; Reardon, C.* ; Lacher, S.M.* ; Ruland, J. ; Ohashi, P.S.* ; Mak, T.W.*

The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells.

J. Clin. Invest. 122, 4698-4709 (2012)
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Effector functions of inflammatory IL-17-producing Th (Th17) cells have been linked to autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). However, what determines Th17 cell encephalitogenicity is still unresolved. Here, we show that after EAE induction, mice deficient for the NF-κB regulator MALT1 (Malt1-/- mice) exhibit strong lymphocytic infiltration in the CNS, but do not develop any clinical signs of EAE. Loss of Malt1 interfered with expression of the Th17 effector cytokines IL-17 and GM-CSF both in vitro and in vivo. In line with their impaired GM-CSF secretion, Malt1-/- Th cells failed to recruit myeloid cells to the CNS to sustain neuroinflammation, whereas autoreactive WT Th cells successfully induced EAE in Malt1-/- hosts. In contrast, Malt1 deficiency did not affect Th1 cells. Despite their significantly decreased secretion of Th17 effector cytokines, Malt1-/- Th17 cells showed normal expression of lineage-specific transcription factors. Malt1-/- Th cells failed to cleave RelB, a suppressor of canonical NF-κB, and exhibited altered cellular localization of this protein. Our results indicate that MALT1 is a central, cell-intrinsic factor that determines the encephalitogenic potential of inflammatory Th17 cells in vivo.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ROR-GAMMA-T; CYTOKINE GM-CSF; TGF-BETA; INFLAMMATORY RESPONSES; TRANSCRIPTION FACTORS; EFFECTOR PHASE; HELPER-CELLS; T(H)17 CELLS; IN-VIVO
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 122, Heft: 12, Seiten: 4698-4709 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Investigation
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)