Attenuated IL-2 muteins leverage the TCR signal to enhance regulatory T cell homeostasis and response in vivo

Frontiers in Immunology

Immunology

Ashutosh Chaudhry¹  Hong Zhou¹  Shiping Lu¹  Michelle So¹  Aazam Ghelani¹  Robyn Hall¹  Wenjun Liu¹  Chi-Ming Li¹  Hao Wu¹  Xin Luo¹  Sue J. Sohn¹  Sherman Yu¹  Shining Ma¹  Elly Song¹  Rohith Srivas¹  Taryn Cariaga¹  Anupama Sahoo¹  Marcus Soto² 

[1] Amgen Research, Amgen Inc., South San Francisco, CA, United States;Amgen Research, Amgen Inc., Thousand Oaks, CA, United States;

关键词: regulatory T cell (Treg);    interleukin-2 (IL-2);    IL-2 therapy;    cytokine;    T cell receptor (TCR);    in vivo;    tolerance;   

DOI  :  10.3389/fimmu.2023.1257652

 received in 2023-07-12, accepted in 2023-09-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

Interleukin-2 (IL-2), along with T-cell receptor (TCR) signaling, are required to control regulatory T cell (Treg) homeostasis and function in vivo. Due to the heightened sensitivity to IL-2, Tregs retain the ability to respond to low-dose or attenuated forms of IL-2, as currently being developed for clinical use to treat inflammatory diseases. While attenuated IL-2 increases Treg selectivity, the question remains as to whether a weakened IL-2 signal sufficiently enhances Treg suppressive function(s) toward disease modification. To understand this question, we characterized the in vivo activity and transcriptomic profiles of two different attenuated IL-2 muteins in comparison with wildtype (WT) IL-2. Our study showed that, in addition to favoring Tregs, the attenuated muteins induced disproportionately robust effects on Treg activation and conversion to effector Treg (eTreg) phenotype. Our data furthermore suggested that Tregs activated by attenuated IL-2 muteins showed reduced dependence on TCR signal, at least in part due to the enhanced ability of IL-2 muteins to amplify the TCR signal in vivo. These results point to a new paradigm wherein IL-2 influences Tregs’ sensitivity to antigenic signal, and that the combination effect may be leveraged for therapeutic use of attenuated IL-2 muteins.

【 授权许可】

Unknown   
Copyright © 2023 Ma, So, Ghelani, Srivas, Sahoo, Hall, Liu, Wu, Yu, Lu, Song, Cariaga, Soto, Zhou, Li, Chaudhry, Luo and Sohn