Nicolas Tchitchek, Michelle Rosenzwajg, Roberta Lorenzon, Darawan Rinchai, Damien Chaussabel, Thomas R Malek, David Klatzmann
These findings demonstrate that IL-2LD 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-2LD therapy.
OBJECTIVES: Low-dose interleukin-2 (IL-2LD) 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-2LD 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-2LD 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-2LD 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-2LD.
CONCLUSIONS: These findings demonstrate that IL-2LD 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-2LD therapy.