Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis
| Autor: | Anthony T. Vella, Antoine Ménoret, Julia Svedova, Reinhard Laubenbacher, Jenny E. Suarez-Ramirez, Linda S. Cauley, Naomi Tsurutani, Adam J. Adler, Forrest B. Treadway, Payal Mittal, Soo Mun Ngoi, Marie-Clare St. Rose |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Immunology Melanoma Experimental Biology CD8-Positive T-Lymphocytes Lymphocyte Activation Article 03 medical and health sciences Interferon-gamma Mice Tumor Necrosis Factor Receptor Superfamily Member 9 Oxygen Consumption Cell Line Tumor Immunology and Allergy Cytotoxic T cell Animals CD134 IL-2 receptor Receptor Cell Proliferation Inflammation Mice Knockout Effector T-cell receptor Receptors Interleukin-1 Cell Differentiation Receptors OX40 Interleukin-12 Cell biology Mice Inbred C57BL 030104 developmental biology Glucose Anaerobic glycolysis Cell culture Interleukin-2 Glycolysis Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 196(1) |
| ISSN: | 1550-6606 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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