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Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

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Abstract
<jats:p>Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5–mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.</jats:p>
Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.
Keywords
Immunology, Immunology and Allergy

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MLA
Whyte, Carly E., et al. “Context-Dependent Effects of IL-2 Rewire Immunity into Distinct Cellular Circuits.” Journal of Experimental Medicine, vol. 219, 2022, doi:10.1084/jem.20212391.
APA
Whyte, C. E., Singh, K., Burton, O. T., Aloulou, M., Kouser, L., Veiga, R. V., … Liston, A. (2022). Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits. Journal of Experimental Medicine, 219. https://doi.org/10.1084/jem.20212391
Chicago author-date
Whyte, Carly E., Kailash Singh, Oliver T. Burton, Meryem Aloulou, Lubna Kouser, Rafael Valente Veiga, Amy Dashwood, et al. 2022. “Context-Dependent Effects of IL-2 Rewire Immunity into Distinct Cellular Circuits.” Journal of Experimental Medicine 219. https://doi.org/10.1084/jem.20212391.
Chicago author-date (all authors)
Whyte, Carly E., Kailash Singh, Oliver T. Burton, Meryem Aloulou, Lubna Kouser, Rafael Valente Veiga, Amy Dashwood, Hanneke Okkenhaug, Samira Benadda, Alena Moudra, Orian Bricard, Stephanie Lienart, Pascal Bielefeld, Carlos P. Roca, Francisco José Naranjo-Galindo, Félix Lombard-Vadnais, Steffie Junius, David Bending, Masahiro Ono, Tino Hochepied, Timotheus Y.F. Halim, Susan Schlenner, Sylvie Lesage, James Dooley, and Adrian Liston. 2022. “Context-Dependent Effects of IL-2 Rewire Immunity into Distinct Cellular Circuits.” Journal of Experimental Medicine 219. doi:10.1084/jem.20212391.
Vancouver
1.
Whyte CE, Singh K, Burton OT, Aloulou M, Kouser L, Veiga RV, et al. Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits. Journal of Experimental Medicine. 2022;219.
IEEE
[1]
C. E. Whyte et al., “Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits,” Journal of Experimental Medicine, vol. 219, 2022.
@article{8762769,
  abstract     = {{<jats:p>Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5–mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.</jats:p>}},
  articleno    = {{e20212391}},
  author       = {{Whyte, Carly E. and Singh, Kailash and Burton, Oliver T. and Aloulou, Meryem and Kouser, Lubna and Veiga, Rafael Valente and Dashwood, Amy and Okkenhaug, Hanneke and Benadda, Samira and Moudra, Alena and Bricard, Orian and Lienart, Stephanie and Bielefeld, Pascal and Roca, Carlos P. and Naranjo-Galindo, Francisco José and Lombard-Vadnais, Félix and Junius, Steffie and Bending, David and Ono, Masahiro and Hochepied, Tino and Halim, Timotheus Y.F. and Schlenner, Susan and Lesage, Sylvie and Dooley, James and Liston, Adrian}},
  issn         = {{0022-1007}},
  journal      = {{Journal of Experimental Medicine}},
  keywords     = {{Immunology,Immunology and Allergy}},
  language     = {{eng}},
  title        = {{Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits}},
  url          = {{http://dx.doi.org/10.1084/jem.20212391}},
  volume       = {{219}},
  year         = {{2022}},
}

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