IL7Rα contributes to experimental autoimmune encephalomyelitis through altered t cell responses and nonhematopoietic cell lineages

Jessica J. Ashbaugh, Roberta Brambilla, Shaffiat A. Karmally, Cecilia Cabello, Thomas R. Malek, John R. Bethea

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. In this study, we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7Rα expression is largely restricted to thymic tissue in IL7RTgIL7R-/- mice. Compared with wild-type (WT) mice, IL7RTgIL7R-/- mice exhibited reduced paralysis and myelin damage that correlated with dampened effector responses, namely decreased TNF production. Furthermore, treatment of diseased WT mice with neutralizing anti-IL7Rα Ab also resulted in significant improvement of EAE. In addition, chimeric mice were generated by bone marrow transplant to limit expression of IL7Rα to cells of either hematopoietic or nonhematopoietic origin. Mice lacking IL7Rα only on hematopoietic cells develop severe EAE, suggesting that IL7Rα expression in the nonhematopoietic compartment contributes to disease. Moreover, novel IL7Rα expression was identified on astrocytes and oligodendrocytes endogenous to the CNS. Chimeric mice that lack IL7Rα only on nonhematopoietic cells also develop severe EAE, which further supports the role of IL7Rα in T cell effector function. Conversely, mice that lack IL7Rα throughout both compartments are dramatically protected from disease. Taken together, these data indicate that multiple cell types use IL7Rα signaling in the development of EAE, and inhibition of this pathway should be considered as a new therapeutic avenue for MS.

Original languageEnglish (US)
Pages (from-to)4525-4534
Number of pages10
JournalJournal of Immunology
Volume190
Issue number9
DOIs
StatePublished - May 1 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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