Interferon-stimulated gene signature predicts clinical response to low-dose IL-2 in immune-mediated inflammatory diseases
Abstract
Objectives Low-dose interleukin-2 (IL-2 LD ) preferentially stimulates regulatory T cells (Treg) over conventional CD4+ T cells (Tconv), controlling inflammation and promoting immune tolerance in autoimmune and other immune-mediated inflammatory diseases. However, IL-2 has pleiotropic functions, and its therapeutic mechanisms of action remain incompletely defined. In addition, the absence of reliable biomarkers of clinical efficacy limits personalised treatment strategies. We therefore aimed to characterise the transcriptomic effects of IL-2 LD in Treg and Tconv cells and to identify candidate biomarkers associated with clinical response. Methods We analysed the whole transcriptome of purified Treg and Tconv from 23 patients with various immune-mediated inflammatory diseases, predominantly autoimmune disorders, treated with IL-2 LD in the TRANSREG open-label, exploratory basket trial (NCT01988506). Peripheral blood samples were collected at baseline, day 8, and month 3 after the initiation of treatment. Gene network analysis and multivariate modelling were performed to explore underlying immunological mechanisms of clinical efficacy and evaluate candidate biomarkers associated with clinical response. Results IL-2 LD induced broad immune transcriptomic changes, predominantly in Treg cells. Beyond expected IL-2-related gene activation, treatment was associated with progressive downregulation of interferon-stimulated genes (ISGs) in both Treg and Tconv cells, including GBP1, IFIT2, IFIT3 , and RSAD2 . Importantly, a multivariate model based on baseline ISG expression showed promise for predicting clinical response status to IL-2 LD . Conclusions These findings demonstrate that IL-2 LD not only expands and activates Treg cells but also shapes an anti-inflammatory transcriptomic landscape characterised by ISG downregulation in Treg and Tconv cells. Baseline ISG expression was associated with treatment response, supporting its evaluation as a candidate biomarker for IL-2 LD therapy.
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BibTeX
@article{tchitchek2026interferonstimulated,
title = {{Interferon-stimulated gene signature predicts clinical response to low-dose IL-2 in immune-mediated inflammatory diseases}},
author = {Nicolas Tchitchek and Michelle Rosenzwajg and Roberta Lorenzon and Darawan Rinchai and Damien Chaussabel and Thomas Malek and David Klatzmann},
journal = {Annals of the Rheumatic Diseases},
year = {2026},
month = oct,
doi = {10.1016/j.ard.2026.07.021},
url = {https://hal.science/hal-05798650v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Interferon-stimulated gene signature predicts clinical response to low-dose IL-2 in immune-mediated inflammatory diseases
AU - Nicolas Tchitchek
AU - Michelle Rosenzwajg
AU - Roberta Lorenzon
AU - Darawan Rinchai
AU - Damien Chaussabel
AU - Thomas Malek
AU - David Klatzmann
PY - 2026
DA - 2026/10/14
JO - Annals of the Rheumatic Diseases
DO - 10.1016/j.ard.2026.07.021
UR - https://hal.science/hal-05798650v1
AB - Objectives Low-dose interleukin-2 (IL-2 LD ) preferentially stimulates regulatory T cells (Treg) over conventional CD4+ T cells (Tconv), controlling inflammation and promoting immune tolerance in autoimmune and other immune-mediated inflammatory diseases. However, IL-2 has pleiotropic functions, and its therapeutic mechanisms of action remain incompletely defined. In addition, the absence of reliable biomarkers of clinical efficacy limits personalised treatment strategies. We therefore aimed to characterise the transcriptomic effects of IL-2 LD in Treg and Tconv cells and to identify candidate biomarkers associated with clinical response. Methods We analysed the whole transcriptome of purified Treg and Tconv from 23 patients with various immune-mediated inflammatory diseases, predominantly autoimmune disorders, treated with IL-2 LD in the TRANSREG open-label, exploratory basket trial (NCT01988506). Peripheral blood samples were collected at baseline, day 8, and month 3 after the initiation of treatment. Gene network analysis and multivariate modelling were performed to explore underlying immunological mechanisms of clinical efficacy and evaluate candidate biomarkers associated with clinical response. Results IL-2 LD induced broad immune transcriptomic changes, predominantly in Treg cells. Beyond expected IL-2-related gene activation, treatment was associated with progressive downregulation of interferon-stimulated genes (ISGs) in both Treg and Tconv cells, including GBP1, IFIT2, IFIT3 , and RSAD2 . Importantly, a multivariate model based on baseline ISG expression showed promise for predicting clinical response status to IL-2 LD . Conclusions These findings demonstrate that IL-2 LD not only expands and activates Treg cells but also shapes an anti-inflammatory transcriptomic landscape characterised by ISG downregulation in Treg and Tconv cells. Baseline ISG expression was associated with treatment response, supporting its evaluation as a candidate biomarker for IL-2 LD therapy.
SN - 0003-4967
SN - 1468-2060
ER -