Research

The research at the Department of Immunology has had a long-standing interest in cytokine immunotherapy, particularly interleukin-2 (IL-2) immunotherapy for the treatment of cancer and autoimmune diseases. IL-2 is a key cytokine for maintaining regulatory T (Treg) cells and peripheral immune tolerance. This motivated us to conduct a clinical trial testing low-dose IL-2 immunotherapy for the treatment of patients with systemic lupus erythematosus. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell programs, including highly proliferative CD38+ HLA-DR+, activated gut-homing CD38+, and skin-homing HLA-DR+ Treg cells (Raeber et al. medRxiv 2022, https://doi.org/10.1101/2022.11.15.22282201). However, the functional properties of tissue-resident human Treg cells in health and disease are incompletely understood. Most of our knowledge stems from mouse models allowing limited translation to humans. Furthermore, their precise function in maintaining peripheral tolerance in different tissues has been scarcely investigated. To close these knowledge gaps, this project aims to investigate i) the diversity of Treg subsets in different human tissues, ii) decipher their tissue-dependent functions, and iii) investigate their properties of maintaining peripheral tolerance by studying Treg dysfunction in various autoimmune diseases. Improved understanding of tissue-resident Treg cells will advance our understanding of the underlying immune dysregulation in different autoimmune diseases, allowing for identification of novel treatment targets and thus guiding future directions of potentially curative treatment approaches allowing to reestablish immune tolerance.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect all major organ systems, often resulting in high disease burden. Despite active research, SLE still remains an incompletely understood disease of unknown pathogenesis and limited treatment options. Regulatory T (Treg) cells are indispensable for maintaining peripheral tolerance and are highly dependent on the cytokine interleukin-2 (IL-2). As regulatory T (Treg) cell insufficiency is common among SLE patients, this motivated us to treat 12 SLE patients with low-dose IL-2. This not only restored Treg cells but revealed several distinct Treg cell programs, including highly proliferative CD38+ HLA-DR+, activated gut-homing CD38+, and skin-homing HLA-DR+ Treg cells (Raeber et al. medRxiv 2022, https://doi.org/10.1101/2022.11.15.22282201). Building on these results, this project aims to i) identify the role of different Treg cell subsets in SLE, ii) decipher the underlying immune dysregulation of specific organ involvement including cutaneous lupus and lupus nephritis, iii) stratify patients based on pathogenic mechanisms, such as type I IFN-driven, B cell-driven, and Treg cell-insufficient phenotypes, and iv) identify biomarkers and develop diagnostic panels to translate potential findings back to clinical application. To complete these aims, we have access to blood and tissue samples from a clinically well-characterized SLE cohort. Comparing different cellular, transcriptional, and protein signatures of SLE patients should allow for identification of signatures stratifying this heterogeneous disease and bears the potential to not only discover specific biomarkers but also novel treatment targets.

As an endeavor to bring cytokine treatment to the clinics, we conducted an investigator-initiated clinical trial, termed Charact-IL-2, testing low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients. The rationale for this trial was based on a functional deficit of regulatory T (Treg) cells in SLE, which could be corrected by exogenous administration of IL-2. Due to expression of the trimeric high-affinity IL-2 receptor, Treg cells respond to low doses of IL-2, whereas effector T cells require high doses due to expression of the intermediate-affinity IL-2 receptor. Our trial reported expansion and skin infiltration of Treg cells coinciding with clinical and serological response in 12 SLE patients treated with low-dose IL-2 over 9 weeks, thus meeting its primary and secondary endpoints. By conducting an in-depth immune phenotyping exploiting recent technological advances in imaging mass cytometry, high-parameter flow cytometry, bulk and single-cell RNA sequencing with cellular indexing and targeted serum proteomics, this work comprises the most comprehensive human study of in vivo effects of IL-2 immunotherapy. Within this study, we gained unprecedented insights into human Treg cell biology and IL-2 immunotherapy, revealing novel Treg cell subsets with distinct gut- and skin-homing properties.