Increased cAMP and cAMP-dependent protein kinase activity mediate anti-CD2 induced suppression of anti-CD3-driven interleukin-2 production and CD25 expression.

TitleIncreased cAMP and cAMP-dependent protein kinase activity mediate anti-CD2 induced suppression of anti-CD3-driven interleukin-2 production and CD25 expression.
Publication TypeJournal Article
Year of Publication1995
AuthorsLin J, Gettys TW, Qin L, Chavin KD, Yang Q, Ding Y, Punch JD, Bromberg JS
Date Published1995
KeywordsAnimals, Antibodies, Monoclonal, CD2 Antigens, CD3 Complex, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Enzyme Activation, Female, Immunoglobulin Fragments, Immunosuppressive Agents, Interleukin-2, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Receptors, Interleukin-2, T-Lymphocytes

Anti-CD2 monoclonal antibody (mAb) can act synergistically with anti-CD3 to produce tolerance and diminish the anti-CD3-induced cytokine syndrome. Since interleukin(IL)-2 production and IL-2 receptor (IL-2R; CD25) expression are important determinants of CD3-driven T cell activation, the effects of anti-CD2 on anti-CD3-induced CD25 expression and IL-2 production were analyzed and related mechanistically to CD2-stimulated cAMP signaling with an in vitro model of T cell activation. The anti-CD2 mAb, 12-15, alone had no effect on splenic T cell CD25 expression and IL-2 production, while the anti-CD3 mAb, 145-2C11, caused significant increases in both CD25 expression and IL-2 production. The addition of anti-CD2 inhibited anti-CD3-induced increases in CD25 and IL-2. The inhibitory signal delivered by anti-CD2 was effective in many forms of T cell activation, since other stimuli which increased CD25, such as concanavalin A, phytohemagglutinin, and Staphylococcal enterotoxin B (SEB), could also be inhibited by anti-CD2. The inhibitory effect of anti-CD2 on CD25 could not be reversed by high doses of supplemental IL-2 added to the culture. Anti-CD2 increased cytoplasmic cAMP in a dose- and time-dependent manner. Reagents that increased cytoplasmic cAMP such as forskolin, cholera toxin, and 3'-isobutyl-1-methylxanthine could mimic the inhibitory effect of anti-CD2 on anti-CD3-driven CD25 expression. Anti-CD2 also increased the activity of cAMP-dependent protein kinase (PKA). H8, a PKA antagonist, blocked the inhibitory effect of anti-CD2 on CD25 expression, further confirming the role of PKA in CD2-induced negative signaling. The use of paired agonists to PKA demonstrated that a type I PKA was the preferential enzyme isoform stimulated by CD2 ligation. These findings show that increased cAMP and PKA activity mediate anti-CD2-induced suppression of anti-CD3-driven IL-2 production and CD25 expression, and provide mechanisms for anti-CD2-induced immunosuppression and inhibition of the cytokine syndrome associated with anti-CD3 treatment.

Alternate JournalPathobiology
PubMed ID8866788
Grant ListAI32655 / AI / NIAID NIH HHS / United States
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Lihui Qin, M.D., Ph.D.

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