The Inducible Costimulator Augments Tc17 Cell Responses to Self and Tumor Tissue

CD8型 癌症研究 细胞生物学 免疫学 兴奋剂 受体 生物 免疫系统 医学 内科学
作者
Michelle H. Nelson,Sreenath Kundimi,Jacob S. Bowers,C.E. Rogers,Logan W. Huff,Kristina M. Schwartz,Krishnamurthy Thyagarajan,Elizabeth C. Little,Shikhar Mehrotra,David J. Cole,Mark P. Rubinstein,Chrystal M. Paulos
出处
期刊:Journal of Immunology [American Association of Immunologists]
卷期号:194 (4): 1737-1747 被引量:44
标识
DOI:10.4049/jimmunol.1401082
摘要

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.
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