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.
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065; jallison@mdanderson.org vpedicord@rockefeller.edu.
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Pedicord
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065; and.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Welby
authors.initials: W
authors.lastname: Montalvo-Ortiz
authors.affiliation: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Miller
authors.affiliation: Department of Immunology, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065; jallison@mdanderson.org vpedicord@rockefeller.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D010047:Ovalbumin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus