title: Preferential expansion of human virus-specific multifunctional central memory T cells by partial targeting of the IL-2 receptor signaling pathway: the key role of CD4+ T cells.
abstract: Effector memory T cells are effective in controlling acute infections, but central memory T cells play a key role in long-lasting protection against viruses and tumors. In vivo/in vitro challenge by Ag commonly supports the generation of effector memory T cells with limited longevity. To our knowledge, this study demonstrates for the first time in the human system and under rechallenge conditions that targeting IL-2R by partial mammalian target of rapamycin inhibition or blocking IL-2Rα enriches human CD4(+)/CD8(+) central memory T cells within the virus-specific T cell product associated with enhanced functionality (i.e., multicytokine secretors, including IL-2; enhanced CD137 and CD107a expression on CD8(+) and CD4(+) T cells, respectively; and killing infected target cells). Remarkably, the effects on CD8(+) T cells are mainly mediated via the enhancement of CD4(+) T cell function. The data reveal new insights into the role of CD4(+) T cell support for the quality of CD8(+) T cell memory, even under rechallenge conditions. Moreover, our method offers a new approach to improve the long-lasting efficacy of adoptive T cell therapy in patients.
authors.affiliation: Institute of Medical Immunology, Charité University Medicine Berlin, 13353 Berlin, Germany. michael.schmueck@charite.de
authors.forename: Michael
authors.initials: M
authors.lastname: Schmueck
authors.forename: Annika M
authors.initials: AM
authors.lastname: Fischer
authors.forename: Ben
authors.initials: B
authors.lastname: Hammoud
authors.forename: Gordon
authors.initials: G
authors.lastname: Brestrich
authors.forename: Henrike
authors.initials: H
authors.lastname: Fuehrer
authors.forename: Si-Hong
authors.initials: SH
authors.lastname: Luu
authors.forename: Karin
authors.initials: K
authors.lastname: Mueller
authors.forename: Nina
authors.initials: N
authors.lastname: Babel
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases