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

Shining Ma; Michelle So; Aazam Ghelani; Rohith Srivas; Anupama Sahoo; Robyn Hall; Wenjun Liu; Hao Wu; Sherman Yu; Shiping Lu; Elly Song; Taryn Cariaga; Marcus Soto; Hong Zhou; Chi-Ming Li; Ashutosh Chaudhry; Xin Luo; Sue J Sohn

doi:10.3389/fimmu.2023.1257652

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

Front Immunol. 2023 Sep 22:14:1257652. doi: 10.3389/fimmu.2023.1257652. eCollection 2023.

Authors

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

Affiliations

¹ Amgen Research, Amgen Inc., South San Francisco, CA, United States.
² Amgen Research, Amgen Inc., Thousand Oaks, CA, United States.

Abstract

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.

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

MeSH terms

Homeostasis
Humans
Interleukin-2* / genetics
Interleukin-2* / metabolism
Receptors, Antigen, T-Cell* / metabolism
Signal Transduction
T-Lymphocytes, Regulatory*

Substances

Interleukin-2
Receptors, Antigen, T-Cell
IL2 protein, human

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. The authors declare that this study received funding from Amgen Research and Development. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.