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

Whyte, C. E.; Singh, K.; Burton, O. T.; Aloulou, M.; Moudra, A.; Roca, C. P.; Naranjo, F. J.; Lombard-Vadnais, F.; Kouser, L.; Hochepied, T.; Halim, T. Y. F.; Schlenner, S.; Lesage, S.; Dooley, J.; Liston, A.

doi:10.1101/2020.12.18.423431

bioRxiv · 10.1101/2020.12.18.423431

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

Whyte, C. E.·Singh, K.·Burton, O. T.·Aloulou, M.·Moudra, A.·Roca, C. P.·Naranjo, F. J.·Lombard-Vadnais, F.·Kouser, L.·Hochepied, T.·Halim, T. Y. F.·Schlenner, S.·Lesage, S.·Dooley, J.·Liston, A.

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Abstract

Interleukin 2 (IL-2) is a key homeostatic cytokine, with potential therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical application has been hampered by pleiotropic functionality and wide-spread receptor expression, with unexpected adverse events during trials. To characterize the IL-2 homeostatic network, we developed a novel mouse strain allowing IL-2 production to be diverted. Rewiring of IL-2 production to diverse leukocyte sources allowed the identification of contextual influences over IL-2 impact. Network analysis identified a priority access for Tregs, and a competitive fitness cost induced among both Tregs and conventional CD4 T cells for IL-2 production. CD8 T cells and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified the Treg circuit, while IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells. The former was associated with an unexpected concentration of rare CD8+ Tregs in B cell zones, while the latter drove a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain unexpected adverse effects observed during clinical trials of exogenous IL-2. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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Whyte, C. E., Singh, K., Burton, O. T., Aloulou, M., Moudra, A., Roca, C. P., Naranjo, F. J., Lombard-Vadnais, F., Kouser, L., Hochepied, T., Halim, T. Y. F., Schlenner, S., Lesage, S., Dooley, J., Liston, A.. 2020-12-20. Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits. https://doi.org/10.1101/2020.12.18.423431

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