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

Anne Brüstle, Dirk Brenner, Christiane B. Knobbe, Philipp A. Lang, Carl Virtanen, Brian M. Hershenfield, Colin Reardon, Sonja M. Lacher, Jürgen Ruland, Pamela S. Ohashi, Tak W. Mak

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75 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4698-4709
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
StatePublished - Dec 3 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. (2012). The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells. Journal of Clinical Investigation, 122(12), 4698-4709. https://doi.org/10.1172/JCI63528