Differential regulation of antigen-driven T cell proliferation and cytokine production by divergent redox mediated cAMP pathways

T cell response to antigenic stimulation is regulated by various intracellular as well as exogenous stimuli. Physiological mechanisms of regulation can often be exploited by use of exogenous substances to achieve optimal regulation of T cell function. An example of this is exists in literature demonstrating suppressive effects of exogenous cAMP on lymphocyte proliferation, secretion of IL-2 and immune effector functions in response to antigen. Importantly, cAMP is also elevated by the cell itself under physiologic conditions, yet the impact of this increase on T cell function is incompletely understood. Another important mechanism of T cell regulation is redox imbalance. Examples of physiologic and experimental alterations of redox potential and T cell function are numerous. Immunosuppressed T cells encountered in HIV-infection, aging, and various other disease states have separately been shown to exhibit both elevated cAMP levels and altered oxidative environments. However, there is an absence of literature to consider a possible link between cAMP-mediated pathways and alteration of redox potential in T cells resulting in hyporesponsiveness and/or “anergy”. In this study, we show that elevation of intracellular cAMP induces a PKA-independent elevation of H2O2 together with oxidation-induced conformational changes and inhibition of critical associations and kinase activities of key signaling molecules. These cAMP-mediated oxidative changes are characterized by direct affects on key antioxidant molecules and enzymes and play a direct role in suppressing the proliferative capacity of TCR-stimulated Th1 cells. Lastly, cAMP is shown to differentially regulate IFNγ secretion by a H2O2-independent, PKA-dependent induction of nitric oxide production. Taken together, we argue that the mechanism of cAMP-mediated suppression of T cell function is distinct from that of classical (costimulation-deprived) T cell anergy. Further, this model of cAMP-mediated redox regulation is useful for the study of biochemical/immunological aspects of AIDS and other disease entities in the absence of compounding influences of viral infection. Ongoing studies in our laboratories will utilize this model to investigate the impact of differential proliferative versus IFNγ production on the clinical onset of experimental autoimmune encephalomyelitis (EAE).