Reference : Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-In...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency
Mosenden, Randi* [> >]
Singh, Pratibha* [> >]
Cornez, Isabelle [> >]
Heglind, Mikael [> >]
Ruppelt, Anja [> >]
MOUTSCHEN, Michel mailto [Centre Hospitalier Universitaire de Liège - CHU > > Maladies infectieuses et médecine interne générale >]
Enerbäck, Sven [> >]
Rahmouni, Souad mailto [Université de Liège - ULg > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén. >]
Tasken, Kjetil [> >]
* These authors have contributed equally to this work.
Journal of Immunology
American Association of Immunologists
Yes (verified by ORBi)
[en] Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE2- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP–type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5–infected RIADtransgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP–type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases.
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