The dual role of the cAMP-dependent protein kinase Cα subunit in T-cell receptor-triggered T-lymphocytes effector functions

In order to directly evaluate the role of the cAMP-dependent protein kinase (PKA) catalytic (C) subunit in T-cell receptor- (TCR) triggered cytotoxic T-lymphocytes (CTL) effector functions, cells were studied after pretreatment with antisense oligomers complementary to mRNA for the Cα or Cβ subunits. Cα subunit is shown to be predominantly expressed in CTL. In some experiments the pretreatment of the CTL with the Cα antisense, but not with the control or Cβ antisense oligomers, resulted in the inhibition of cAMP-independent PKA activity without significantly affecting the level of total cAMP-inducible PKA activity. In parallel assays, CTL which were pretreated with the Cα antisense oligomer had enhanced antigen-bearing target cell-triggered-, anti-TCR monoclonal antibody-triggered-, and phorbol 12-myristate 13-acetate/ A23187-triggered exocytosis of granules, as well as enhanced antigen-specific cytotoxicity. In contrast, the TCR-triggered γ-interferon mRNA expression and γ-interferon secretion were inhibited in Cα antisense-pretreated CTL. These results suggest that the Cα subunit of PKA may have a dual role in regulation of T-lymphocytes effector functions: (i) it may down-regulate TCR-triggered protein-synthesis independent responses such as cytotoxicity and exocytosis, thereby counteracting TCR-triggered activation even in the absence of the second messenger, cAMP, and (ii) the Cα subunit activity is likely to be required for the nuclear and/or cytoplasmic events in CTL's activation involved in lymphokine synthesis and secretion.