title: The inducible costimulator augments Tc17 cell responses to self and tumor tissue.
abstract: The inducible costimulator (ICOS) plays a key role in the development of Th17 cells, but its role in the development and antitumor activity of IL-17-producing CD8(+) T cells (Tc17) remains unknown. We found that ICOS costimulation was important for the functional maintenance, but not differentiation, of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist mAb or by using recipient mice genetically deficient in the ICOS ligand reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, activating Tc17 cells with an ICOS agonist in vitro enhanced their capacity to eradicate melanoma and induce autoimmune vitiligo when infused into mice. However, ICOS stimulation did not augment the antitumor activity of IL-2 expanded T cells. Additional investigation revealed that ICOS stimulation not only increased IL-2Rα, CXCR3, and IL-23R expression on Tc17 cells, but also dampened their expression of suppressive molecule CD39. Although Tc17 cells activated with an ICOS agonist cosecreted heightened IL-17A, IL-9, and IFN-γ, their therapeutic effectiveness was critically dependent on IFN-γ production. Depletion of IL-17A and IL-9 had little impact on antitumor Tc17 cells activated with an ICOS agonist. Collectively, our work reveals that the ICOS pathway potentiates the antitumor activity of adoptively transferred Tc17 cells. This work has major implications for the design of vaccine, Ab and cell-based therapies for autoimmunity, infectious disease, and cancer.
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and nelsonmh@musc.edu paulos@musc.edu.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Nelson
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Sreenath
authors.initials: S
authors.lastname: Kundimi
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Bowers
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Rogers
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Logan W
authors.initials: LW
authors.lastname: Huff
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Schwartz
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Thyagarajan
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Little
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425; and Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425 nelsonmh@musc.edu paulos@musc.edu.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17