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

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

Author information

1
Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065; jallison@mdanderson.org vpedicord@rockefeller.edu.
2
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065; and.
3
Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
4
Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

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.

PMID:
25624453
DOI:
10.4049/jimmunol.1402390
[Indexed for MEDLINE]
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