A reengineered common chain cytokine augments CD8+ T cell-dependent immunotherapy.
Author
Banerjee, AnirbanLi, Dongge
Guo, Yizhan
Mei, Zhongcheng
Lau, Christine
Chen, Kelly
Westwick, John
Klauda, Jeffery B
Schrum, Adam
Lazear, Eric R
Krupnick, Alexander S
Date
2022-05-23Journal
JCI InsightPublisher
American Society for Clinical InvestigationType
Article
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Show full item recordAbstract
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.Identifier to cite or link to this item
http://hdl.handle.net/10713/18994ae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.158889
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