title: 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.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: D'Souza
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Parish
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Sharen E
authors.initials: SE
authors.lastname: McKay
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut. Electronic address: gerald.shadel@yale.edu.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000150:complications / Q000276:immunology / Q000821:virology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D019409:Interleukin-15 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008216:Lymphocytic Choriomeningitis / Q000150:complications / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019409:Interleukin-15; D046912:Multiprotein Complexes; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus