title: The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells.
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.
authors.affiliation: The Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.forename: Christiane B
authors.initials: CB
authors.lastname: Knobbe
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.forename: Brian M
authors.initials: BM
authors.lastname: Hershenfield
authors.forename: Colin
authors.initials: C
authors.lastname: Reardon
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Lacher
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D020169:Caspases / Q000172:deficiency / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D059748:Proteolysis; D018417:Th1 Cells / Q000276:immunology / Q000502:physiology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051841:Transcription Factor RelB / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22; D000098546:Interleukin-21
chemical_list: D020169:Caspases; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020381:Interleukin-17; D007378:Interleukins; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D051841:Transcription Factor RelB; D014157:Transcription Factors; D000097043:Interleukin-22; D000098546:Interleukin-21; C497594:Relb protein, mouse; C498509:Malt1 protein, mouse