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

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 NIKG2D but signaled through the common gamma 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 !ow-affinity antigens, activated nuclear factor of activated T cells transcription factors, and promoted mitochondria! biogenesis. OMCPmutIL-2 thus outperformed other common y chain cytokines as a catalyst for in vitro CD8(+) T cell expansion and in vivo CD8(+) T cell-based immunotherapy.

Automated summary

This article describes a potentially unique cytokine designed to separate T cell surface binding and signaling, thus improving the side effects and cell exhaustion associated with cytokine therapy. The fusion protein cytokine showed precise activation of cytotoxic T cells, improved their survival and memory cell generation, and decreased exhaustion. This functional improvement was achieved through altered signal transduction pathways, which increased CD8(+) T cell response to low-affinity antigens, activated transcription factors, and promoted mitochondria biogenesis.