INFLUENCE OF CD28 CO-STIMULATION ON CYTOKINE PRODUCTION IS MAINLY REGULATED VIA INTERLEUKIN-2

Interaction of CD28 with its ligand B7 plays an important role in the initiation of immune responses. The co-stimulatory signal generated by cross-linking of CD28 molecules results in enhanced T-cell proliferat ion and augmentation of cytokine production. In particular, mRNA level s of T-helper 1 (Th1)-type cytokines, such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) are reported to be strongly increased. W e investigated the effect of CD28 co-stimulation on the production of Th2-type cytokines. CD28 mAb induced a strong augmentation of IL-2 sec retion in activated T-cell clones. Production of IFN-gamma was also en hanced, but the increase in IL-4 secretion was generally moderate. Aug mentation of IL-4 production by CD28 was most pronounced in clones tha t produced low amounts of IL-2, compared to clones producing high leve ls of IL-2. It was found that the up-regulation of IL-4 by CD28 co-sti mulation was mainly controlled indirectly via an increase of IL-2. Som e clones could produce IL-4 in an IL-2-independent manner; in these si tuations CD28 co-stimulation had no augmenting effect on the productio n of IL-4. The secretion of IL-4 by peripheral blood CD4(+) T cells, t hat were activated with B7-expressing transfectants, was also found to be dependent on IL-2. Finally, Northern blot analysis confirmed that costimulation of CD28 primarily affected IL-2 production, and that inh ibition of IL-2/IL-2 receptor interaction abolished the augmenting act ion of CD28 monoclonal antibody on the production of the Th2-type cyto kines IL-4, IL-5 and IL-10 and of the Th1 cytokine IFN-gamma.