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The Interleukin 12 (IL-12) family of cytokines is comprised of heterodimeric proteins including IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (IL27p28/Ebi3) and IL-35 (p35/Ebi3). IL-27p28 and IL-12p40 have recently been shown to antagonize IL-27 and IL-12 functions, respectively, suggesting that single chain IL-12 family members may act as dominant-negative inhibitors of IL-12 family heterodimeric cytokines. Here, we have genetically engineered IL-12p35 (rIL-12p35) and examined whether IL-12p35 has biological activities independent of its partner, IL-12p40 or EBI3. We show that rIL-12p35 blocked IL-6 mediated activation of STAT1 and STAT3 pathways of TCR-activated CD4+ T cells and inhibited the expansion of Th17 but not Th1 cells. Of particular significance, rIL-12p35 protected mice from autoimmune uveitis by inhibiting pathogenic Th17 cell expansion. Our study demonstrates that IL-12p35 can be used to modulate IL-6-mediated signaling pathways and treat a CNS autoimmune disease.