Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 45, Issue 10, Pages 2780-2786Publisher
WILEY
DOI: 10.1002/eji.201545800
Keywords
Experimental autoimmune encephalomyelitis; IL-12; IL-23; Th1 cells; Th17 cells
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Funding
- NIH [R01 NS057670, T32-AI007413, 5T32GM7863-34]
- University of Michigan Rackham Merit Fellowship
- Veterans Administration Merit Review Awards [1I01RX000416, 1I01BX001387]
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CD4(+) T-helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL-23 is universally required for the acquisition of pathogenic properties by myelin-reactive T cells. We show that IL-12-modulated Th1 cells readily produce IFN- and GM-CSF in the CNS of mice and induce a severe form of EAE via an IL-23-independent pathway. Th1-mediated EAE is characterized by monocyte-rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL-23-modulated, stable Th17 cells induce EAE with a relatively mild course via an IL-12-independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4(+) T-helper-cell subsets and polarizing factors.
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