J. Exp. Med., Volume 189, Number 6, March 15, 1999 969-978

Regulation of Interleukin (IL)-12 Receptor 2 Subunit Expression by Endogenous IL-12: A Critical Step in the Differentiation of Pathogenic Autoreactive T Cells

By John T. Chang, Ethan M. Shevach, and Benjamin M. Segal

From the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

The interleukin (IL)-12 receptor (R)2 subunit is the critical molecule involved in maintaining IL-12 responsiveness and controlling T helper cell type 1 lineage commitment. We demonstrate that IL-12 and interferon (IFN)- play separate, but complementary, roles in regulating IL-12R2 expression on antigen-specific CD4⁺ T cells. These results are consistent with our previous observation that IL-12 can promote autoimmune disease through IFN--independent as well as -dependent pathways. Therefore, we compared the induction of IL-12 by, and the expression of the IL-12R2 subunit on, myelin basic protein (MBP)-specific T cells from experimental allergic encephalomyelitis (EAE)-susceptible SJL (H-2^s) mice and from EAE- resistant B10.S mice (H-2^s). B10.S mice had an antigen-specific defect in their capacity to upregulate the IL-12R2 subunit. Defective expression was not secondary to the production of suppressive cytokines, but to a failure of B10.S MBP-specific T cells to upregulate CD40 ligand expression and to induce the production of IL-12. IL-12R2 expression as well as encephalitogenicity of these cells could be restored by the addition of IL-12. These results suggest that the development of immunotherapies that target the IL-12R2 subunit may be useful for the treatment of autoimmune diseases.

autoimmunity;  experimental allergic encephalomyelitis;  T helper cell type 1 lymphocytes;  interferon ;  CD40 ligand

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