Regulatory T cells (Treg) are crucial for the maintenance of peripheral tolerance and for the control of ongoing inflammation and autoimmunity. The cytokine interleukin-2 (IL-2) is essentially required for the growth and survival of Treg in the peripheral lymphatic tissues and thus plays a vital role in the biology of Treg. Most autoimmune and rheumatic diseases exhibit disturbances in Treg biology either at a numerical or functional level resulting in an imbalance between protective and pathogenic immune cells. In addition, in some autoimmune diseases, a relative deficiency of IL-2 develops during disease pathogenesis leading to a disturbance of Treg homeostasis, which further amplifies the vicious cycle of tolerance breach and chronic inflammation. Low-dose IL-2 therapy aims either to compensate for this IL-2 deficiency to restore a physiological state or to strengthen the Treg population in order to be more effective in counter-regulating inflammation while avoiding global immunosuppression. Here we highlight key findings and summarize recent advances in the clinical translation of low-dose IL-2 therapy for the treatment of autoimmune and rheumatic diseases.

BackgroundA defect in regulatory T cell (Treg) homeostasis due to an acquired deficiency of interleukin-2 (IL-2) plays an important role in the pathogenesis of systemic lupus erythematosus (SLE).1,2 However, it is still unclear whether a defect in the Treg-IL-2 axis is also involved in other connective tissue disease such as inflammatory myopathies or primary Sjogren´s syndrome (pSS).ObjectivesThe aim of our study was to investigate whether Treg from patients with poly- and dermatomyositis (PM/DM) and pSS display typical features of IL-2 deficiency in parallel to phenotypic alterations of conventional CD4+ T cell (Tcon) subsets compared to healthy controls (HC).MethodsPBMC were isolated from patients with PM/DM (n=22) and pSS (n=17) and from age- and sex-matched HC (n=19) using gradient density centrifugation. Treg and Tcon subsets were analyzed by using multicolor flow cytometry. Mann-Whitney test was used for statistical analyses.ResultsFrequencies of FoxP3+CD127lo Treg among CD3+CD4+T cells were higher in pSS compared to PM/DM patients (p<0.001) and to HC (p<0.05). However, in both, PM/DM and pSS patients, frequencies of CD25+ cells among FoxP3+CD127lo Treg were significantly lower compared to HC (PM/DM: p<0.05, pSS: p<0.0001), while the frequencies of Helios+ cells among the CD25- Treg subset were substantially higher in pSS patients compared to DM/PM and HC (both p<0.001). Conversely, we found lower frequencies of CXCR5+ follicular Treg only in PM/DM patients (p<0.05). In parallel, there were higher frequencies of CD45RO+CCR7- effector/memory cells (p<0.01) and of Ki67+ proliferating cells (p<0.05) among CD3+CD4+FoxP3- Tcon in pSS patients compared to HC, which was not observed in PM/DM patients.ConclusionThe loss of the CD25+ Treg subset in PM/DM and pSS patients is similar to previous findings in SLE patients1 and represents a hallmark of IL-2 deficiency. This suggests that shortage of IL-2 is pathophysiologically relevant also in PM/DM and pSS providing a rationale for low-dose IL-2 therapy in these diseases. In addition, activation and expansion of effector/memory Tcon appears to be more pronounced in pSS compared to PM/DM. The different distribution of Treg and of Tcon subsets between pSS and PM/DM patients might reflect differences in the availability of IL-2 and in the regulation of Tcon responses in these diseases.References[1]von Spee-Mayer C, Siegert E, Abdirama D, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2016; 75; 1407–1415.[2]Humrich JY, von Spee-Mayer C, Siegert E, et al. Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial. Lancet Rheumatol. 2019; 1; e44-e54Disclosure of InterestsLuisa R. Monne: None declared, Sara Comduehr: None declared, Fynn Gerlach: None declared, Antje Müller: None declared, Gabriela Riemekasten: None declared, Jens Y. Humrich Speakers bureau: GSK, AstraZeneca, Pfizer, BMS, UCB, MSD, AbbVie, Consultant of: GSK, AstraZeneca, ILTOO Pharma, Selecta Biosciences, Janssen-Cilag, Grant/research support from: Sanofi