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ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.

Dysregulation of T follicular helper (Tfh) and T follicular regulatory (Tfr) cell homeostasis in germinal centers (GCs) can lead to antibody-mediated autoimmunity. While IL-1β modulates the GC response via IL-1R1 and IL-1R2 receptors on follicular T cells in animal models, its role in humans remains unclear. We analyzed Tfh and Tfr phenotypes in human secondary lymphoid organs (tonsils, spleen, and mesenteric lymph nodes) using flow cytometry, single-cell transcriptomics, and in vitro culture, comparing findings with samples from autoimmune patients. We observed organ-specific Tfh/Tfr phenotypes according to activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 expression promoted a unique activated Tfr subset with Treg and GC-Tfh features. IL-1β signaling via IL-1R1 enhanced follicular T cell activation and Tfh-to-Tfr differentiation, while IL-1β inhibition upregulated IL-1R1, indicating a tightly regulated process. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with increased autoantibody production, linking inflammation, IL-1β signaling, and Tfr/Tfh balance. Our findings highlight the critical role of IL-1β in follicular T cell activation and suggest that targeting IL-1β signaling in Tfh and Tfr cells could be a promising strategy for treating antibody-mediated autoimmune diseases.

Objective : Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. Aim : We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. Methods : We performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. Results : ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. Conclusion : The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.

INTRODUCTION:Autoimmune and autoinflammatory diseases (AIDs) represent a socioeconomic burden as the second cause of chronic illness in Western countries. In this context, the TRANSIMMUNOM clinical protocol is designed to revisit the nosology of AIDs by combining basic, clinical and information sciences. Based on classical and systems biology analyses, it aims to uncover important phenotypes that cut across diagnostic groups so as to discover biomarkers and identify novel therapeutic targets.METHODS AND ANALYSIS:TRANSIMMUNOM is an observational clinical protocol that aims to cross-phenotype a set of 19 AIDs, six related control diseases and healthy volunteers . We assembled a multidisciplinary cohort management team tasked with (1) selecting informative biological (routine and omics type) and clinical parameters to be captured, (2) standardising the sample collection and shipment circuit, (3) selecting omics technologies and benchmarking omics data providers, (4) designing and implementing a multidisease electronic case report form and an omics database and (5) implementing supervised and unsupervised data analyses.ETHICS AND DISSEMINATION:The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De-France 48-15) and done in accordance with the Declaration of Helsinki and good clinical practice. Written informed consent is obtained from all participants before enrolment in the study. TRANSIMMUNOM's project website provides information about the protocol (https://www.transimmunom.fr/en/) including experimental set-up and tool developments. Results will be disseminated during annual scientific committees appraising the project progresses and at national and international scientific conferences.DISCUSSION:Systems biology approaches are increasingly implemented in human pathophysiology research. The TRANSIMMUNOM study applies such approach to the pathophysiology of AIDs. We believe that this translational systems immunology approach has the potential to provide breakthrough discoveries for better understanding and treatment of AIDs.

Pain is the hallmark symptom of osteoarthritis (OA) and its biological drivers remain poorly understood. While the role of innate immunity in OA has been extensively studied, the involvement of adaptive immunity, in particular regulatory T cells (Tregs), is not well understood. Using a comprehensive multi-omic approach on the peripheral blood from 46 knee OA patients with similar radiographic stage, including deep immunophenotyping, cytokine profiling, transcriptomic and T-cell receptor analysis on sorted CD4 Tregs and effector T cells (Teff), we identified an immunological signature associated with OA-related pain. Cytokines promoting Treg expansion and activation (with increases of sIL2-RA, sTNFR1, sTNFR2) were correlated with the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscore, suggesting a potential Treg dysfunction. Nineteen T cell subsets were correlated with WOMAC pain. Notably, we found a negative correlation of cell subsets associated with Treg expansion and activation (FoxP3+CTLA4+, CD4+CD57+, Treg CD95+, CD4 Treg CD45RA-). Differential gene expression analysis between patients with low and high WOMAC pain intensity (threshold ≥ 40/100) revealed an upregulation of inflammasome-related genes such as IL1RL1, IL31RA, IFITM3, NLRP3, IFNG in Tregs. Functional enrichment analysis highlighted an overrepresentation of innate immune response, IL-8, and interferon activation pathways suggesting a pro-inflammatory state in Tregs of patients with high pain intensity. Collectively, our systems immunology approach highlights multiple associations between Treg dysfunctionality and OA-related pain, providing new insights into the adaptive immune system’s contribution to OA-related pain.

Dysregulation of the T follicular helper (Tfh) and T follicular regulatory (Tfr) homeostasis in the germinal center (GC) can result in antibody-mediated autoimmunity. While interleukin-1β (IL-1β) has been shown to be an important modulator of the GC response in animal models via the expression of IL-1 agonist (IL-1R1) and antagonist (IL-1R2) receptors on follicular T cells, such regulation has not yet been studied in humans. We investigated Tfh and Tfr phenotypes in human secondary lymphoid organs — namely tonsils, spleens, and mesenteric lymph nodes — using flow cytometry, single-cell transcriptomics, and in vitro cell culture. We also benchmarked our findings with a cohort of patients with autoimmune and inflammatory diseases. We found that Tfh and Tfr cells exhibit organ-specific phenotypes related to their activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 was linked to the emergence of a unique activated Tfr subset that combines features of both Treg and GC-Tfh cells. Single-cell transcriptomics and in vitro studies showed that IL-1β signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1β resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1β signaling, and the Tfr/Tfh balance. Our study underscores the pivotal role of IL-1β in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1β signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.