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. 2011 Jun;178(6):2740-51. doi: 10.1016/j.ajpath.2011.02.022.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ataxia Telangiectasia / complications
  • Ataxia Telangiectasia / immunology
  • Ataxia Telangiectasia / virology*
  • Ataxia Telangiectasia Mutated Proteins
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology*
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Immunologic Memory / drug effects
  • Immunologic Memory / immunology*
  • Interleukin-15 / pharmacology
  • Lymphocyte Activation / drug effects
  • Lymphocytic Choriomeningitis / complications
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / drug effects
  • Lymphocytic choriomeningitis virus / immunology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Interleukin-15
  • Multiprotein Complexes
  • Proteins
  • Receptors, Antigen, T-Cell
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus