The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells
Anne Brüstle, … , Pamela S. Ohashi, Tak W. Mak
Anne Brüstle, … , Pamela S. Ohashi, Tak W. Mak
Published November 1, 2012
Citation Information: J Clin Invest. 2012;122(12):4698-4709. https://doi.org/10.1172/JCI63528.
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Research Article Immunology

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

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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Figure 1

Malt1–/– mice are resistant to EAE induction.

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Malt1–/– mice are resistant to EAE induction. (A) Malt1–/– (n = 9) an...
(A) Malt1–/– (n = 9) and WT (n = 11) mice were immunized s.c. with MOG peptide in CFA, followed by i.p. injection of PT. Disease severity was scored daily. Data are the mean score ± SEM and are representative of 2 independent experiments. (B and C) Representative histopathological analyses of cross-sections of (B) brain and (C) spinal cord from mice in A at 30 days after MOG injection. Brain and spinal cord sections were stained with H&E (B and C) or immunostained to detect CD3+ T cells (B and C) or B220+ B cells (B). Scale bars: 100 μm. Data are from 1 mouse per group, representative of 2 independent experiments. (D) CNS-infiltrating CD4+ T cells from brains and spinal cords of Malt1–/– and WT mice were isolated by gradient centrifugation on day 14 after EAE induction. Expression levels of IL-17A and IFN-γ were analyzed by intracellular staining and flow cytometry. Data are gated on live CD4+ T cells. Also shown is quantitation of percent brain- and spinal cord–infiltrating CD4+ T cells producing IFN-γ and IL-17. Data are mean ± SEM (n = 4 per group).