INTERLEUKIN-12 AND B7 CD28 INTERACTION SYNERGISTICALLY UP-REGULATE INTERLEUKIN-10 PRODUCTION BY HUMAN T-CELLS/

Interleukin 12 (IL-12) is a heterodimeric cytokine which promotes the development of Th1 cells and their interferon gamma (IFN-gamma) produc tion after TCR/CD3 triggering, Previous reports indicate that IL-12 sy nergizes with accessory signalling through B7/CD28 interaction in indu cing proliferation and IFN-gamma production by human T cells, In this study, we investigated the capacity of IL-12 to modify cytokine synthe sis by freshly purified human peripheral blood T cells stimulated with anti-CD3 as the primary signal and with CD80 on transfected mouse cel ls as an accessory signal, Our data demonstrate that IL-12 indeed syne rgizes with B7/CD28 interaction, not only in inducing IFN-gamma produc tion, but also in enhancing IL-10 synthesis in a dose-dependent manner , In contrast, IL-4 and IL-5 production were slightly inhibited by IL- 12, The effect of IL-12 on the secretion of IL-10 was confirmed by sti mulating T cells in the absence of accessory cells with immobilized an ti-CD3 mAb and soluble anti-CD28 mAb, CD80 and IL-12 mainly costimulat ed CD4(+)CD45RO(+) T cells but not CD8(+) or CD45RA(+) T cells to prod uce IL-10, Cyclosporin A (CsA) partially inhibited, and a neutralizing anti-IL-2 mAb in combination with anti-IL-2R mAbs (anti-Tac and Mik b eta 1) strongly reduced IL-10 production, On the other hand, IL-12 did not affect IL-2 production. The data thus suggest a model in which op timal IL-10 production by stimulated peripheral blood T cells results from the co-operation of IL-12, B7/CD28 interaction and the ensuing IL -2 activity. (C) 1997 Academic Press Limited.