title: Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.
abstract: Adoptive cellular therapy (ACT) with the Th17 subset of CD4+T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8+T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Neitzke
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Bowers
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Andrijauskaite
authors.affiliation: Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: O'Connell
authors.affiliation: Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wrangle
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.affiliation: Departments of Surgery, and Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Hollings Cancer Center Room 506, Charleston, SC, 29425, USA. markrubinstein@musc.edu.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016219:Immunotherapy, Adoptive; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology* / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7
keywords: ACT; IL-15; IL-2; IL-7; Th17 cells