Cyclic AMP Sensitive Signalling by the CD28 Marker Requires Concomitant Stimulation by the T‐Cell Antigen Receptor (TCR/CD3) Complex

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Abstract
We have previously demonstrated that activation of cAMP‐dependent protein kinase (cAK) type I (cAKI, RIα2‐Cβ2) mediates the inhibitory effects of cAMP on T‐cell replication induced through the TCR/CD3 complex. In the present study we have investigated the effect of cAMP on T‐cell DNA synthesis, tyrosine phosphorylation of a 100 kDa protein (pp100) and IL2 mRNA expression, induced through stimulation of the TCR/CD3‐ and/or the CD28 molecules. Our results demonstrate that tyrosine phosphorylation of pp100 stimulated by anti‐CD3 is inhibited by cAMP both in the presence and absence of the phorbol ester PMA, and reflects the changes seen in IL2 mRNA expression and T‐cell replication. Combined stimulation with anti‐CD3 and anti‐CD28, which gives a synergistic response in T‐cell replication, gave pp100 phosphorylation and IL2 mRNA expression sensitive to cAMP‐dependent inhibition. When PMA was added in addition to anli‐CD3 and anti‐CD28, the inhibitory effect of cAMP on both T‐cell replication and pp100 phosphorylation was completely abolished. The fact that pp100 phosphorylation in response to TCR/CD3‐, CD28‐ and PMA stimulation and cAMP mediated inhibition are identical to the effects of the same stimuli on T‐cell proliferation, makes this protein an interesting candidate in downstream signalling from these receptors. In addition, our results are compatible with a model where cAMP, through activation of cAKI, eliminates both the PTK and PKC activating capability of the T‐cell receptor at a site(s) proximal to PKC activation. Furthermore, the CD28 molecule which activates PTKs, enters the PTK cascade at a point distal to the target(s) for cAKI action. Therefore, during CD28 signalling PKC activation can be achieved either by TCR/CD3 stimulation (inhibited by cAMP), or directly by PMA (not inhibited by cAMP)