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

• DOI: 10.1172/jci.insight.158889
• Publication Date: 2022-05-22T18:00:55Z
• Authors: Anirban Banerjee; Dongge Li; Yizhan Guo; Zhongcheng Mei; Christine Lau; Kelly Chen; John Westwick; Jeffery B. Klauda; Adam Schrum; Eric R. Lazear; Alexander S. Krup...
• Keywords: ZAP70

Cytokine therapy is limited by undesirable off-target side effects as well terminal differentiation and exhaustion of chronically stimulated T cells. Here, we describe the signaling properties a potentially unique cytokine design, where cell surface binding are separated between 2 different families receptors. This fusion protein cytokine, called OMCPmutIL-2, bound with high affinity to cytotoxic lymphocyte-defining immunoreceptor NKG2D but signaled through common γ chain receptor. In addition precise activation cells due redirected binding, OMCPmutIL-2 resulted in superior both human murine CD8+ improving their survival memory generation decreasing exhaustion. functional improvement was direct result altered signal transduction based on reorganization membrane lipid rafts that led Janus kinase-3–mediated phosphorylation receptor rather than STAT/AKT intermediates. novel pathway increased response low-affinity antigens, activated nuclear factor transcription factors, promoted mitochondrial biogenesis. thus outperformed other cytokines catalyst for vitro expansion vivo cell–based immunotherapy.