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Friends Not Foes: CTLA-4 Blockade and mTOR Inhibition Cooperate during CD8+ T Cell Priming To Promote Memory Formation and Metabolic Readiness

Virginia A. Pedicord, Justin R. Cross, Welby Montalvo-Ortiz, Martin L. Miller and James P. Allison
J Immunol January 26, 2015, 1402390; DOI: https://doi.org/10.4049/jimmunol.1402390
Virginia A. Pedicord
*Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
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Justin R. Cross
†Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065; and
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Welby Montalvo-Ortiz
*Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
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Martin L. Miller
‡Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065
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James P. Allison
*Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
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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.

Footnotes

  • This work was supported in part by the Howard Hughes Medical Institute.

  • The microarray data presented in this article have been submitted to National Center for Biotechnology Information’s Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE63022) under accession number GSE63022.

  • The online version of this article contains supplemental material.

  • Received September 18, 2014.
  • Accepted December 30, 2014.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 209 (4)
The Journal of Immunology
Vol. 209, Issue 4
15 Aug 2022
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Friends Not Foes: CTLA-4 Blockade and mTOR Inhibition Cooperate during CD8+ T Cell Priming To Promote Memory Formation and Metabolic Readiness
Virginia A. Pedicord, Justin R. Cross, Welby Montalvo-Ortiz, Martin L. Miller, James P. Allison
The Journal of Immunology January 26, 2015, 1402390; DOI: 10.4049/jimmunol.1402390

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Friends Not Foes: CTLA-4 Blockade and mTOR Inhibition Cooperate during CD8+ T Cell Priming To Promote Memory Formation and Metabolic Readiness
Virginia A. Pedicord, Justin R. Cross, Welby Montalvo-Ortiz, Martin L. Miller, James P. Allison
The Journal of Immunology January 26, 2015, 1402390; DOI: 10.4049/jimmunol.1402390
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