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 proliferation and augmentation of cytokine production. In particular, mRNA levels of T-helper 1 (Th1)-type cytokines, such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) are reported to be strongly increased. We investigated the effect of CD28 co-stimulation on the production of Th2-type cytokines. CD28 mAb induced a strong augmentation of IL-2 secretion in activated T-cell clones. Production of IFN-gamma was also enhanced, but the increase in IL-4 secretion was generally moderate. Augmentation of IL-4 production by CD28 was most pronounced in clones that produced low amounts of IL-2, compared to clones producing high levels of IL-2. It was found that the up-regulation of IL-4 by CD28 co-stimulation was mainly controlled indirectly via an increase of IL-2. Some clones could produce IL-4 in an IL-2-independent manner; in these situations CD28 co-stimulation had no augmenting effect on the production of IL-4. The secretion of IL-4 by peripheral blood CD4+ T cells, that were activated with B7-expressing transfectants, was also found to be dependent on IL-2. Finally, Northern blot analysis confirmed that co-stimulation of CD28 primarily affected IL-2 production, and that inhibition of IL-2/IL-2 receptor interaction abolished the augmenting action of CD28 monoclonal antibody on the production of the Th2-type cytokines IL-4, IL-5 and IL-10 and of the Th1 cytokine IFN-gamma.
Kuiper
H M
HM
Central Laboratory, Netherlands Red Cross Blood Transfusion Service, Amsterdam.
de Jong
R
R
Brouwer
M
M
Lammers
K
K
Wijdenes
J
J
van Lier
R A
RA
D015152:Blotting, Northern; D018106:CD28 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis*; D007700:Kinetics; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D016207:Cytokines; D007376:Interleukin-2; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma