Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis

Hong Zhang, Joseph R. Podojil, Xunrong Luo, Stephen D. Miller

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Multiple sclerosis is characterized by perivascular CNS infiltration of myelin-specific CD4+ T cells and activated mononuclear cells. TCR transgenic mice on the SJL background specific for proteolipid protein (PLP)139-151 develop a high incidence of spontaneous experimental autoimmune encephalomyelitis (sEAE). We examined the intrinsic mechanisms regulating onset and severity of sEAE. CD4+ T cells isolated from the cervical lymph nodes, but not spleens, of diseased 5B6 transgenic mice are hyperactivated when compared with age-matched healthy mice and produce both IFN-γ and IL-17, indicating that the cervical lymph node is the initial peripheral activation site. The age-associated development of sEAE correlates with a decline in both the functional capacity of natural regulatory T cells (nTregs) and in PLP139-151-induced IL-10 production and a concomitant increase in IL-17 production. Anti-CD25-induced inactivation of nTregs increased the incidence and severity of sEAE. Conversely, induction of peripheral tolerance via the i.v. injection of PLP139-151-pulsed, ethylcarbodiimide-fixed APCs (PLP139-151-SP) inhibited the development of clinical disease concomitant with increased production of IL-10 and conversion of Foxp3+ Tregs from CD4+CD25- progenitors. These data indicate that heterogeneous populations of Tregs regulate onset of sEAE, and that induction of peripheral tolerance can be exploited to prevent/treat spontaneous autoimmune disease.

Original languageEnglish (US)
Pages (from-to)4638-4647
Number of pages10
JournalJournal of Immunology
Volume181
Issue number7
DOIs
StatePublished - Oct 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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