Abstract
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 naïve 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 naïve, 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.
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Ataxia Telangiectasia / complications
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Ataxia Telangiectasia / immunology
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Ataxia Telangiectasia / virology*
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Ataxia Telangiectasia Mutated Proteins
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / enzymology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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Cell Cycle Proteins / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / immunology*
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Cell Proliferation / drug effects
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Enzyme Activation / drug effects
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Immunologic Memory / drug effects
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Immunologic Memory / immunology*
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Interleukin-15 / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocytic Choriomeningitis / complications
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic Choriomeningitis / virology
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Lymphocytic choriomeningitis virus / drug effects
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Lymphocytic choriomeningitis virus / immunology*
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / metabolism
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Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Interleukin-15
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Multiprotein Complexes
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Proteins
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Receptors, Antigen, T-Cell
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Tumor Suppressor Proteins
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus