Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 7, Pages 4638-4647Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.7.4638
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Funding
- NCRR NIH HHS [UL1 RR025741] Funding Source: Medline
- NINDS NIH HHS [NS-048411, R01 NS048411, R01 NS048411-04, R01 NS-026543, R01 NS026543, R01 NS026543-20] Funding Source: Medline
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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)(131-151) 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-gamma 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.
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