Control of cAMP Levels Is Implicated in Normal and Diseased TCell Function

PKA is activated upon TCR-induced cAMP production in lipid rafts and inhibits proximal T-cell signaling. However, overexpression of PDE4 isoforms or P-arrestin has been demonstrated to increase T-cell activation, revealing regulatory roles for both proteins in T-cell signaling (Abrahamsen et al. 2004). Other regulatory roles for P-arrestin in T cells have also been described. For example, P-arrestin plays a positive regulatory role in chemotaxis (Fong et al. 2002) and in migration into the airways during asthma (Walker et al. 2003). The activities of both PKA and PDE4 therefore seem to be important for regulation of TCR-induced signaling and T-cell function. We propose a novel role for TCR and CD28 co-stimulation in down-modulation of TCR-induced cAMP-mediated inhibitory signals through the recruitment of ß-arrestin and PDE4 to lipid rafts and thus allowing a full T-cell response to occur. Interestingly, the cAMP inhibitory pathway has also been shown to be implicated in several immune diseases. T cells from HIV-infected patients have elevated levels of cAMP and hyperactivation of PKA. Targeting of the cAMP-PKA type-I pathway by selective antagonists reverses T-cell dysfunction in HIV T cells ex vivo (Aandahl et al. 1998, 1999), and targeting cyclooxygenase 2 to reduce PGE2 production lowers cAMP and increases T-cell function in vivo (Johansson et al. 2004; Kvale et al. 2006). A similar mechanism contributes to the T-cell dysfunction in a subset of patients with common variable immunodeficiency (Aukrust et al. 1999) and to the severe T-cell anergy in a murine immunodeficiency model termed MAIDS (mouse AIDS) (Rahmouni et al. 2004, 2001).

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