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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 bet...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220948/
https://www.ncbi.nlm.nih.gov/pubmed/35603788
http://dx.doi.org/10.1172/jci.insight.158889
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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.
author_facet 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.
author_sort Banerjee, Anirban
collection PubMed
description 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.
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spelling pubmed-92209482022-06-24 A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy 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. JCI Insight Research Article 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. American Society for Clinical Investigation 2022-05-23 /pmc/articles/PMC9220948/ /pubmed/35603788 http://dx.doi.org/10.1172/jci.insight.158889 Text en © 2022 Banerjee et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
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.
A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy
title A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy
title_full A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy
title_fullStr A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy
title_full_unstemmed A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy
title_short A reengineered common chain cytokine augments CD8(+) T cell–dependent immunotherapy
title_sort reengineered common chain cytokine augments cd8(+) t cell–dependent immunotherapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220948/
https://www.ncbi.nlm.nih.gov/pubmed/35603788
http://dx.doi.org/10.1172/jci.insight.158889
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