Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming to promote memory formation and metabolic readiness

J Immunol. 2015 Mar 1;194(5):2089-98. doi: 10.4049/jimmunol.1402390. Epub 2015 Jan 26.

Abstract

During primary Ag encounter, T cells receive numerous positive and negative signals that control their proliferation, function, and differentiation, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mammalian target of rapamycin inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8(+) T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8(+) T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8(+) T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mammalian target of rapamycin inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation, and an optimal metabolic program for CD8(+) T cell memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / microbiology
  • CD8-Positive T-Lymphocytes / pathology
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology*
  • Cell Differentiation
  • Cell Proliferation
  • Gene Expression Regulation
  • Immunologic Memory*
  • Listeria monocytogenes / immunology
  • Listeriosis / genetics
  • Listeriosis / immunology*
  • Listeriosis / microbiology
  • Listeriosis / pathology
  • Lymphocyte Activation
  • Lymphoma / genetics
  • Lymphoma / immunology*
  • Lymphoma / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Ovalbumin / genetics
  • Ovalbumin / immunology
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology*

Substances

  • Antibodies, Monoclonal
  • CTLA-4 Antigen
  • Ovalbumin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus

Associated data

  • GEO/GSE63022