Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells

Dirk Brenner, Anne Brüstle, Gloria H Y Lin, Philipp A. Lang, Gordon S. Duncan, Christiane B. Knobbe-Thomsen, Michael ST Paul, Colin Reardon, Michael W. Tusche, Bryan Snow, Sara R. Hamilton, Aline Pfefferle, Syed O. Gilani, Pamela S. Ohashi, Karl S. Lang, Tak W. Mak

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been linked to apoptosis, IgM binding, and innate immune responses. In this study, we used Toso-deficient mice to investigate the importance of Toso in tolerance and autoimmunity. We found that Toso-/- mice do not develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model for the human disease multiple sclerosis. Toso-/- dendritic cells were less sensitive to Toll-like receptor stimulation and induced significantly lower levels of disease-associated inflammatory T-cell responses. Consistent with this observation, the transfer of Toso-/- dendritic cells did not induce autoimmune diabetes, indicating their tolerogenic potential. In Toso-/- mice subjected to EAE induction, we found increased numbers of regulatory T cells and decreased encephalitogenic cellular infiltrates in the brain. Finally, inhibition of Toso activity in vivo at either an early or late stage of EAE induction prevented further disease progression. Taken together, our data identify Toso as a unique regulator of inflammatory autoimmune responses and an attractive target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)1060-1065
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number3
DOIs
StatePublished - Jan 21 2014
Externally publishedYes

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Keywords

  • Inflammation
  • Th1/Th17 cells

ASJC Scopus subject areas

  • General

Cite this

Brenner, D., Brüstle, A., Lin, G. H. Y., Lang, P. A., Duncan, G. S., Knobbe-Thomsen, C. B., Paul, M. ST., Reardon, C., Tusche, M. W., Snow, B., Hamilton, S. R., Pfefferle, A., Gilani, S. O., Ohashi, P. S., Lang, K. S., & Mak, T. W. (2014). Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America, 111(3), 1060-1065. https://doi.org/10.1073/pnas.1323166111/-/DCSupplemental