| First Author | D'Souza AD | Year | 2011 |
| Journal | Am J Pathol | Volume | 178 |
| Issue | 6 | Pages | 2740-51 |
| PubMed ID | 21641396 | Mgi Jnum | J:173475 |
| Mgi Id | MGI:5014129 | Doi | 10.1016/j.ajpath.2011.02.022 |
| Citation | D'Souza AD, et al. (2011) Aberrant CD8(+) T-Cell Responses and Memory Differentiation upon Viral Infection of an Ataxia-Telangiectasia Mouse Model Driven by Hyper-Activated Akt and mTORC1 Signaling. Am J Pathol 178(6):2740-51 |
| abstractText | Immune system-related pathology is common in ataxia-telangiectasia (A-T) patients and mice that lack the protein kinase, A-T mutated (ATM). However, it has not been studied how ATM influences immune responses to a viral infection. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we show that ATM(-/-) mice, despite having fewer naive CD8(+) T cells, effectively clear the virus. However, aberrant CD8(+) T-cell responses are observed, including defective expansion and contraction, effector-to-memory differentiation, and a switch in viral-epitope immunodominance. T-cell receptor-activated, but not naive, ATM(-/-) splenic CD8(+) T cells have increased ribosomal protein S6 and Akt phosphorylation and do not proliferate well in response to IL-15, a cytokine important for memory T-cell development. Accordingly, pharmacological Akt or mammalian target of rapamycin complex 1 (mTORC1) inhibition during T-cell receptor activation alone rescues the IL-15 proliferation defect. Finally, rapamycin treatment during LCMV infection in vivo increases the number of memory T cells in ATM(-/-) mice. Altogether, these results show that CD8(+) T cells lacking ATM have hyperactive Akt and mTORC1 signaling in response to T-cell receptor activation, which results in aberrant cytokine responses and memory T-cell development. We speculate that similar signaling defects contribute to the immune system pathology of A-T, and that inhibition of Akt and/or mTORC1 may be of therapeutic value. |
