OBJECTIVE: Interleukin 15 (IL)-15 controls proliferation and survival of T cells, but its effects and the underlying cellular regulation are not well understood. Previous studies have focused on its effects on short-term T-cell cultures. In view of the potential problems associated with using IL-2 alone in adoptive immunotherapy protocols, we investigated the impact of IL-15 on T-cell cultures and the global transcriptional effects it elicits in such cultures. MATERIALS AND METHODS: DNA microarrays and flow cytometry were used to examine the differential effect of 20 ng/mL IL-15 on primary serum-free T-cell cultures activated and cultured in the presence of IL-2. Quantitative reverse transcriptase polymerase chain reaction confirmed select microarray data. RESULTS: IL-15 significantly increased ex vivo expansion of primary human T cells over the entire 11-day expansions without affecting viability. The 1133 genes were consistently differentially expressed among three donor samples. Ontological analysis demonstrated that IL-15 increases expression of genes involved in inflammatory response (e.g., tumor necrosis factor [TNF]-alpha, Oncostatin M, CD40L, and CD33) and apoptosis (e.g., TNF-related apoptosis-inducing ligand). IL-15 also induced expression of four suppressors of cytokine signaling (SOCS) family genes (SOCS1-3, cytokine-inducible SH2-containing protein), which are classical negative regulators of cytokine signaling. IL-15 strongly suppressed the expression of inhibitory natural killer cell receptor genes, including three C-type lectins (KLRB1, KLRC1, and KLRD1), as well as IL-7Ra and Granzyme H. Finally, IL-15 induced differential expression of TNF receptor superfamily members (CD27 and CD30). CONCLUSION: These findings suggest that exogenous IL-15 may have a potential role in adoptive immunotherapy by both enhancing proliferation and modulating functionality during ex vivo T-cell expansion.
OBJECTIVE:Interleukin 15 (IL)-15 controls proliferation and survival of T cells, but its effects and the underlying cellular regulation are not well understood. Previous studies have focused on its effects on short-term T-cell cultures. In view of the potential problems associated with using IL-2 alone in adoptive immunotherapy protocols, we investigated the impact of IL-15 on T-cell cultures and the global transcriptional effects it elicits in such cultures. MATERIALS AND METHODS: DNA microarrays and flow cytometry were used to examine the differential effect of 20 ng/mL IL-15 on primary serum-free T-cell cultures activated and cultured in the presence of IL-2. Quantitative reverse transcriptase polymerase chain reaction confirmed select microarray data. RESULTS:IL-15 significantly increased ex vivo expansion of primary human T cells over the entire 11-day expansions without affecting viability. The 1133 genes were consistently differentially expressed among three donor samples. Ontological analysis demonstrated that IL-15 increases expression of genes involved in inflammatory response (e.g., tumor necrosis factor [TNF]-alpha, Oncostatin M, CD40L, and CD33) and apoptosis (e.g., TNF-related apoptosis-inducing ligand). IL-15 also induced expression of four suppressors of cytokine signaling (SOCS) family genes (SOCS1-3, cytokine-inducible SH2-containing protein), which are classical negative regulators of cytokine signaling. IL-15 strongly suppressed the expression of inhibitory natural killer cell receptor genes, including three C-type lectins (KLRB1, KLRC1, and KLRD1), as well as IL-7Ra and Granzyme H. Finally, IL-15 induced differential expression of TNF receptor superfamily members (CD27 and CD30). CONCLUSION: These findings suggest that exogenous IL-15 may have a potential role in adoptive immunotherapy by both enhancing proliferation and modulating functionality during ex vivo T-cell expansion.
Authors: C Vitale; C Romagnani; A Puccetti; D Olive; R Costello; L Chiossone; A Pitto; A Bacigalupo; L Moretta; M C Mingari Journal: Proc Natl Acad Sci U S A Date: 2001-04-24 Impact factor: 11.205
Authors: Raquel Tarazona; Olga DelaRosa; Javier G Casado; Julián Torre-Cisneros; José L Villanueva; María D Galiani; José Peña; Rafael Solana Journal: AIDS Date: 2002-01-25 Impact factor: 4.177
Authors: S E Nicholson; D De Souza; L J Fabri; J Corbin; T A Willson; J G Zhang; A Silva; M Asimakis; A Farley; A D Nash; D Metcalf; D J Hilton; N A Nicola; M Baca Journal: Proc Natl Acad Sci U S A Date: 2000-06-06 Impact factor: 11.205
Authors: Pani A Apostolidis; Stephan Lindsey; William M Miller; Eleftherios T Papoutsakis Journal: Physiol Genomics Date: 2012-05-01 Impact factor: 3.107
Authors: Masaki Kashiwada; Deborah M Levy; Lisa McKeag; Keri Murray; Andreas J Schröder; Stephen M Canfield; Geri Traver; Paul B Rothman Journal: Proc Natl Acad Sci U S A Date: 2009-12-22 Impact factor: 11.205
Authors: Jason C Steel; Charmaine A Ramlogan; Ping Yu; Yoshio Sakai; Guido Forni; Thomas A Waldmann; John C Morris Journal: Cancer Res Date: 2010-01-19 Impact factor: 12.701
Authors: Mark L Parrish; Chris Wright; Yarek Rivers; David Argilla; Heather Collins; Brendan Leeson; Andrey Loboda; Michael Nebozhyn; Matthew J Marton; Serguei Lejnine Journal: J Transl Med Date: 2010-09-25 Impact factor: 5.531
Authors: Toni Whistler; Cheng-Feng Chiang; William Lonergan; Mark Hollier; Elizabeth R Unger Journal: BMC Genomics Date: 2010-09-14 Impact factor: 3.969
Authors: Afam Okoye; Haesun Park; Mukta Rohankhedkar; Lia Coyne-Johnson; Richard Lum; Joshua M Walker; Shannon L Planer; Alfred W Legasse; Andrew W Sylwester; Michael Piatak; Jeffrey D Lifson; Donald L Sodora; Francois Villinger; Michael K Axthelm; Joern E Schmitz; Louis J Picker Journal: J Exp Med Date: 2009-06-22 Impact factor: 14.307