| First Author | Mosenden R | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 9 | Pages | 5119-30 |
| PubMed ID | 21430226 | Mgi Jnum | J:172863 |
| Mgi Id | MGI:5009154 | Doi | 10.4049/jimmunol.1100003 |
| Citation | Mosenden R, et al. (2011) Mice with disrupted type I protein kinase A anchoring in T cells resist retrovirus-induced immunodeficiency. J Immunol 186(9):5119-30 |
| abstractText | 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 PGE(2)- 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 RIAD-transgenic 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. |
