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 4

Malt1–/– Th17 cells are not encephalitogenic.

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Malt1–/– Th17 cells are not encephalitogenic. (A) Malt1–/– mice were ...
(A) Malt1–/– mice were injected with 1 × 105 WT 2D2 CD4+ cells or PBS as control. EAE was initiated, and animals were monitored as in Figure 1A. Data (mean ± SEM) are representative of 2 independent experiments. (B) Histopathological analyses of CNS cross-sections from mice in A at 30 days after MOG injection, showing cerebellar white matter, cerebellar cortex, and leptomeningeal blood vessels. Brain sections were stained with H&E or immunostained to detect CD3 (T cells), Mac3 (macrophages), or GFAP (reactive astrocytes). Scale bars: 100 μm. Data are representative of 2 independent experiments. (C) EAE was initiated in Malt1–/– and WT mice by MOG injection. At 10 days after injection, CD4+ T cells from spleens and LNs were isolated and cultured for 5 days with MOG peptide, IL-23, and anti–IFN-γ before injection (2 × 107 cells/mouse) into WT recipients (n = 7 per group). Recipients were injected with PT on the day of T cell transfer and 2 days thereafter. Mice were monitored daily as in Figure 1A. (D and E) Cells generated as in C were injected into transgenic CD45.1+ WT recipients. At day 18 after injection, mice were sacrificed, and CD4+CD45.2+ T cells from spleens and LNs were analyzed for CD40L surface expression (D) and IFN-γ and IL-17A production (E) by intracellular flow cytometry. DP, double IFN-γ/IL-17A producers. Data are mean ± SEM (n = 6).