ROLE OF IL-12 AND 4-1BB LIGAND IN CYTOKINE PRODUCTION BY CD28(-) T-CELLS() AND CD28()

The costimulatory receptor CD28 is important in the development of bot h Th1 and Th2 responses. To further assess the requirement for CD28 in the development of Th1 and Th2 responses, we analyzed the ability of T cells from wild-type or CD28(-) mice to secrete cytokines in MLRs wi th B lymphomas. We find that in the absence of added IL-12, B lymphoma s expressing the alternate costimulatory ligand 4-1BBL can support the production of IL-2 and IL-4 but little detectable IFN-gamma by alloge neic CD28(+) and CD28(-) T cells. IL-4 production by CD28(+) or CD28(- ) T cells responding to B7(low) B lymphomas was abrogated by blocking 4-1BB ligand-4-1BB interaction. When APC express high levels of B7 fam ily molecules as well as 4-1BBL, soluble 4-1BB inhibits IL-4 productio n by CD28(-) but not by CD28(+) cells. Addition of IL-12 to the CD28(- ) MLRs results in increased production of IFN-gamma and decreased amou nts of IL-2 and IL-4. Thus, both Th1 and Th2 responses can develop in the complete absence of a signal through the CD28 molecule. CD28(+) an d CD28(-) T cells differed, however, with respect to the effect of IL- 12 on IL-4 production. IL-12 severely curtailed the amount of IL-4 pro duced in the CD28(-) T cell cultures but had a less profound effect on the level of IL-4 produced in the CD28(+) cultures, suggesting that a strong signal through the CD28 molecule prevents down-regulation of I L-4 production by IL-12.