INCREASED CAMP AND CAMP-DEPENDENT PROTEIN-KINASE ACTIVITY MEDIATE ANTI-CD2 INDUCED SUPPRESSION OF ANTI-CD3-DRIVEN INTERLEUKIN-2 PRODUCTION AND CD25 EXPRESSION
Jx. Lin et al., INCREASED CAMP AND CAMP-DEPENDENT PROTEIN-KINASE ACTIVITY MEDIATE ANTI-CD2 INDUCED SUPPRESSION OF ANTI-CD3-DRIVEN INTERLEUKIN-2 PRODUCTION AND CD25 EXPRESSION, Pathobiology, 63(4), 1995, pp. 175-187
Anti-CD2 monoclonal antibody (mAb) can act synergistically with anti-C
D3 to produce tolerance and diminish the anti-CD3-induced cytokine syn
drome. Since interleukin(IL)-2 production and IL-2 receptor (IL-2R; CD
25) expression are important determinants of CD3-driven T cell activat
ion, the effects of anti-CD2 on anti-CD3-induced CD25 expression and I
L-2 production were analyzed and related mechanistically to CD2-stimul
ated cAMP signaling with an in vitro model of T cell activation. The a
nti-CD2 mAb, 12-15, alone had no effect on splenic T cell CD25 express
ion and IL-2 production, while the anti-CD3 mAb, 145-2Cl1, caused sign
ificant increases in both CD25 expression and IL-2 production. The add
ition of anti-CD2 inhibited anti-CD3-induced increases in CD25 and IL-
2. The inhibitory signal delivered by anti-CD2 was effective in many f
orms of T cell activation, since other stimuli which increased CD25, s
uch as concanavalin A, phytohemagglutinin, and Staphylococcal enteroto
xin B (SEE), could also be inhibited by anti-CD2. The inhibitory effec
t of anti-CD2 on CD25 could not be reversed by high doses of supplemen
tal 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-methylxanthi
ne could mimic the inhibitory effect of anti-CD2 on anti-CD3-driven CD
25 expression. Anti-CD2 also increased the activity of cAMP-dependent
protein kinase (PKA). H8, a PKA antagonist, blocked the inhibitory eff
ect 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 sti
mulated by CD2 ligation. These findings show that increased cAMP and P
KA 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 ass
ociated with anti-CD3 treatment.