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    A reengineered common chain cytokine augments CD8+ T cell-dependent immunotherapy.

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    Author
    Banerjee, Anirban
    Li, Dongge
    Guo, Yizhan
    Mei, Zhongcheng
    Lau, Christine
    Chen, Kelly
    Westwick, John
    Klauda, Jeffery B
    Schrum, Adam
    Lazear, Eric R
    Krupnick, Alexander S
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    Date
    2022-05-23
    Journal
    JCI Insight
    Publisher
    American Society for Clinical Investigation
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1172/jci.insight.158889
    Abstract
    Cytokine therapy is limited by undesirable off-target side effects as well as terminal differentiation and exhaustion of chronically stimulated T cells. Here, we describe the signaling properties of a potentially unique cytokine by design, where T cell surface binding and signaling are separated between 2 different families of receptors. This fusion protein cytokine, called OMCPmutIL-2, bound with high affinity to the cytotoxic lymphocyte-defining immunoreceptor NKG2D but signaled through the common γ chain cytokine receptor. In addition to precise activation of cytotoxic T cells due to redirected binding, OMCPmutIL-2 resulted in superior activation of both human and murine CD8+ T cells by improving their survival and memory cell generation and decreasing exhaustion. This functional improvement was the direct result of altered signal transduction based on the reorganization of surface membrane lipid rafts that led to Janus kinase-3-mediated phosphorylation of the T cell receptor rather than STAT/AKT signaling intermediates. This potentially novel signaling pathway increased CD8+ T cell response to low-affinity antigens, activated nuclear factor of activated T cells transcription factors, and promoted mitochondrial biogenesis. OMCPmutIL-2 thus outperformed other common γ chain cytokines as a catalyst for in vitro CD8+ T cell expansion and in vivo CD8+ T cell-based immunotherapy.
    Keyword
    Cytokines
    Immunology
    Immunotherapy
    Therapeutics
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18994
    ae974a485f413a2113503eed53cd6c53
    10.1172/jci.insight.158889
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