MOLECULAR REGULATION OF HUMAN INTERLEUKIN-2 AND T-CELL FUNCTION BY INTERLEUKIN-4

Distinct functional T-cell subsets, differing in the patterns of lymph okines produced, regulate cell-mediated and humoral immune responses. The two major types and their principal products, interleukin 4 and in terferon gamma (IL-4 and IFN-gamma), are reciprocally negatively inter active. To analyze the molecular mechanism of IL-4-mediated suppressio n of cell-mediated immunity we studied its effects on expression of in terleukin 2 (IL-2) and IFN-gamma. IL-4 pretreatment of Jurkat cells pr ior to stimulation resulted in a decrease in transcription of the IL2 gene. IL-4 suppressed IL-2 and IFN-gamma mRNA levels in primary human T cells, and addition of anti-CD28 antibodies relieved this suppressio n. Using enhancer-reporter constructs, IL-4 specifically down-regulate d the NFIL-2B element. Electrophoretic mobility shift assays using a D NA oligomer containing the NFIL-2B binding site indicated that IL-4 in hibited the NFIL-2B complex and that the NFIL-2B DNA binding factor is distinct from AP-1. These results suggest that IL-4 may regulate deve lopment and function of T-cell subsets involved in cell-mediated immun ity in part by inhibiting factors required for transcription of the IL 2 gene.