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Inhibition of Th1 Polarization by Soluble TNF Receptor Is Dependent on Antigen-Presenting Cell-Derived IL-12¹

Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

Th1-polarized CD4⁺ T cells are considered central to the development of a number of target-directed autoimmune disorders including multiple sclerosis. The APC-derived cytokine IL-12 is a potent inducer of Th1 polarization in T cells. Inhibition of IL-12 in vivo blocks the development of experimental allergic encephalomyelitis, the animal model for multiple sclerosis. Based on previous work that suggests that the production of IL-12 by activated human central nervous system-derived microglia is regulated by autocrine TNF-, we wanted to determine whether inhibition of TNF could induce a reduction of Th1 responses by its impact on systemic APCs. We found that soluble TNFR p75-IgG fusion protein (TNFR:Fc) inhibited production of IFN- by allo-Ag-activated blood-derived human CD4 T cells. We documented reduced IL-12 p70 production by APCs in the MLR. By adding back recombinant IL-12, we could rescue IFN- production, indicating that TNFR:Fc acts on APC-derived IL-12. Consistent with an inhibition of the Th1 polarization, we found a decreased expression of IL-12R-ß₂ subunit on the T cells. Furthermore, the capacity of T cells to secrete IFN- upon restimulation when previously treated with TNFR:Fc is impaired, whereas IL-2 secretion was not altered. Our results define a TNF-dependent cytokine network that favors development of Th1 immune responses.

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