title: Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis.
abstract: CD134- and CD137-primed CD8 T cells mount powerful effector responses upon recall, but even without recall these dual-costimulated T cells respond to signal 3 cytokines such as IL-12. We searched for alternative signal 3 receptor pathways and found the IL-1 family member IL-36R. Although IL-36 alone did not stimulate effector CD8 T cells, in combination with IL-12, or more surprisingly IL-2, it induced striking and rapid TCR-independent IFN-γ synthesis. To understand how signal 3 responses functioned in dual-costimulated T cells we showed that IL-2 induced IL-36R gene expression in a JAK/STAT-dependent manner. These data help delineate a sequential stimulation process where IL-2 conditioning must precede IL-36 for IFN-γ synthesis. Importantly, this responsive state was transient and functioned only in effector T cells capable of aerobic glycolysis. Specifically, as the effector T cells metabolized glucose and consumed O2, they also retained potential to respond through IL-36R. This suggests that T cells use innate receptor pathways such as the IL-36R/axis when programmed for aerobic glycolysis. To explore a function for IL-36R in vivo, we showed that dual costimulation therapy reduced B16 melanoma tumor growth while increasing IL-36R gene expression. In summary, cytokine therapy to eliminate tumors may target effector T cells, even outside of TCR specificity, as long as the effectors are in the correct metabolic state.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Naomi
authors.initials: N
authors.lastname: Tsurutani
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Payal
authors.identifier: http://orcid.org/0000-0002-5754-3108
authors.initials: P
authors.lastname: Mittal
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Marie-Clare
authors.initials: MC
authors.lastname: St Rose
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Soo Mun
authors.initials: SM
authors.lastname: Ngoi
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Julia
authors.identifier: http://orcid.org/0000-0003-0836-4725
authors.initials: J
authors.lastname: Svedova
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Antoine
authors.initials: A
authors.lastname: Menoret
authors.affiliation: Center for Quantitative Medicine, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030.
authors.forename: Forrest B
authors.initials: FB
authors.lastname: Treadway
authors.affiliation: Center for Quantitative Medicine, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Laubenbacher
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Jenny E
authors.identifier: http://orcid.org/0000-0001-9616-5624
authors.initials: JE
authors.lastname: Suárez-Ramírez
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Cauley
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Adler
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and vella@uchc.edu.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Vella
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010101:Oxygen Consumption; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053262:Receptors, OX40 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
chemical_list: D005947:Glucose; D007371:Interferon-gamma; D018664:Interleukin-12; D007376:Interleukin-2; D017472:Receptors, Interleukin-1; D053262:Receptors, OX40; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C505717:Tnfrsf4 protein, mouse; C569500:Il1rl2 protein, mouse