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


Authors: Pedicord, V. A.; Cross, J. R.; Montalvo Ortiz, W.; Miller, M. L.; Allison, J. P.
Article Title: Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming to promote memory formation and metabolic readiness
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. Copyright © 2015 by The American Association of Immunologists, Inc.
Keywords: signal transduction; controlled study; nonhuman; cd8+ t lymphocyte; lymphocyte proliferation; animal cell; mouse; cytotoxic t lymphocyte antigen 4 antibody; enzyme inhibition; animal experiment; animal model; in vivo study; lymphocyte differentiation; nucleotide sequence; mammalian target of rapamycin; tumor cell; cytotoxic t lymphocyte antigen 4; rapamycin; mitochondrion; lymphocyte function; biogenesis; immunization; memory t lymphocyte; cell priming; cell respiration; cellular parameters; priority journal; article
Journal Title: Journal of Immunology
Volume: 194
Issue: 5
ISSN: 0022-1767
Publisher: The American Association of Immunologists, Inc  
Date Published: 2015-03-01
Start Page: 2089
End Page: 2098
Language: English
DOI: 10.4049/jimmunol.1402390
PROVIDER: scopus
PUBMED: 25624453
DOI/URL:
Notes: Export Date: 2 April 2015 -- Source: Scopus
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MSK Authors
  1. James P Allison
    129 Allison
  2. Martin Lee Miller
    14 Miller
  3. Justin Robert Cross
    49 Cross