Impact of Diverse Ion Channels on Regulatory T Cell Functions

The population of regulatory T cells (Tregs) is critical for immunological self-tolerance and homeostasis. Proper ion regulation contributes to Treg lineage identity, regulation, and effector function. Identified ion channels include Ca2+ release-activated Ca2+, transient receptor potential, P2X, volume-regulated anion and K+ channels Kv1.3 and KCa3.1. Ion channel modulation represents a promising therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This review summarizes studies with gene-targeted mice and pharmacological modulators affecting Treg number and function. Furthermore, participation of ion channels is illustrated and the power of future research possibilities is discussed.

Nicotine level associated with decreasing Treg number in smoker healthy volunteers

The intensity of cigarette exposure is associated with the severity of the inflammatory reaction. Treg cell plays a role in suppressing the inflammatory response. There has been no clear evidence on the relationship between smoker behavior with the nicotine level and Treg number. We will investigate the relationship between smoking behavior with the nicotine level and Treg number. We conducted a cross-sectional study of 106 healthy volunteers in Yogyakarta. We interviewed the subjects and took their blood samples for hemogram, Treg number, nicotine level, and blood chemistry examination. The inclusion criteria were fit, male or female, aged 18 years or older, and willing to volunteer proven by completing and signing the informed consent. We collected the data on smoking habits through interviews guided by a questionnaire. We examined hemogram and blood chemistry using a spectrophotometer, while the levels of nicotine were measured using The enzyme-linked immunosorbent assay (ELISA). We described the characteristics of the subjects by univariate analysis. The bivariate analysis was to determine the relationship between cigarette smoking length with nicotine level and Treg number. The results show a connection between the range of tobacco and cigarette number with nicotine levels in the blood with a value of <em>r</em>=0.63 in the Pearson correlation test p&lt;0.00. It can be concluded that there is a relationship between behavior smoking with nicotine levels and Treg counts.

Regulatory T Cell Metabolism in Atherosclerosis

Regulatory T cells (Tregs) are capable of suppressing excessive immune responses to prevent autoimmunity and chronic inflammation. Decreased numbers of Tregs and impaired suppressive function are associated with the progression of atherosclerosis, a chronic inflammatory disease of the arterial wall and the leading cause of cardiovascular disease. Therefore, therapeutic strategies to improve Treg number or function could be beneficial to preventing atherosclerotic disease development. A growing body of evidence shows that intracellular metabolism of Tregs is a key regulator of their proliferation, suppressive function, and stability. Here we evaluate the role of Tregs in atherosclerosis, their metabolic regulation, and the links between their metabolism and atherosclerosis.

The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells

The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.

P0400DECREASED REGULATORY B CELLS AND THEIR ASSOCIATION WITH CLINICAL RESPONSE IN PATIENTS WITH NEW ONSET LUPUS NEPHRITIS

Background and Aims Studies in lupus nephritis (LN) have shown impairment in both T regulatory (Treg) number and function. However, the data on B regulatory (Breg) is limited in LN. Our objective was to study Breg and Treg populations in newly diagnosed treatment naïve LN and study their change after initiation of immunosuppression. Method Study included 25 patients of newly diagnosed LN of Class III (+V), IV (+V), V and 10 healthy controls (HC). Immunophenotyping was performed for peripheral blood mononuclear cell (PBMCs) samples using fluorochrome labelled monoclonal antibodies for Tregs (CD3+CD4+CD25hiCD127loFoxP3+) and Bregs (CD19+CD5+CD1dhi IL-10+). The cells were expressed as percentage of T and B cells. Each lymphocyte population was analysed at baseline, 2 and 6 months after initiation of immunosuppression which was given as per unit protocol. Results Bregs were significantly decreased compared to HC at baseline (p=0.002). With immunosuppression, Bregs showed significant increase at 2 and 6 months (p=0.008) and from baseline to 6 months (p=0.005). Bregs in responders significantly increased from 2 to 6 months (p= 0.017) and from baseline to 6 month (p=0.020), while they did not in non-responders. Tregs did not differ significantly from HC and did not show significant increase at 2 and 6 months, in both responders and non-responders. Conclusion Breg population in newly diagnosed LN was significantly reduced and increased significantly with immunosuppression. Bregs had an association with renal remission. This underscores the potential role of Bregs in the pathophysiology of LN and their association with clinical response. This could aid in the design of new immunotherapies for treatment of lupus nephritis.

Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications

Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment.

Regulatory T-cells and their impacts on cytokine profile of end-stage renal disease patients suffering from systemic lupus erythematosus

Autoimmunity is an identified factor for development of end-stage renal disease (ESRD). Regulatory T-cells (Tregs) play a fundamental role in preventing autoimmunity. This study aimed to determine Treg frequency and its effects on cytokine profile of ESRD patients with and without systemic lupus erythematosus (SLE). Moreover, this study also determines how Treg number is affected by blood transfusion and gender. Peripheral blood mononuclear cells were isolated from 26 ESRD and 10 healthy subjects and stained with anti-CD4, anti-CD25, and anti-FoxP3 antibodies. Treg frequencies in ESRD patients with and without blood transfusion were determined by flow cytometry. Antibodies against human leukocyte antigens (HLAs) were investigated by panel-reactive antibodies screening. Tumor growth factor (TGF)-β1, interleukin (IL)-4, IL-10, TNF-α, IL-17A, and interferon (IFN)-γ serum levels in participants were measured by enzyme-linked immunoasorbent assay (ELISA). ESRD patients with SLE, unlike the patients without SLE, showed a significant reduction in Treg percentage compared to healthy subjects ( P < 0.01). All women had a reduced number of Tregs compared to men. Treg number was significantly decreased in ESRD patients with HLA antibodies ( P < 0.05). Blood transfusion enhanced Treg development in ESRD patients without SLE, unlike the patients with SLE ( P < 0.05). ESRD patients with low Treg showed a reduction in TGF-β1 and IL-4 and an increase in TNF-α and IL-17A levels compared to control groups ( P < 0.05–0.0001). However, no change was observed in IL-10 and IFN-γ levels. Treg frequency was negatively associated with the age of patients ( P < 0.01), while this association was not observed in healthy subjects. Based on these findings, it can be observed that reduction in Treg number may contribute to ESRD development in patients with SLE.

Immune Dysregulation after Cardiothoracic Surgery and Incidental Thymectomy: Maintenance of Regulatory T Cells despite Impaired Thymopoiesis

Thymectomy is performed in infants during cardiothoracic surgery leaving many patients with reduced thympopoiesis. An association between immune disorders and regulatory T cells (Treg) after incidental thymectomy has not been investigated. Questionnaires soliciting symptoms of atopic or autoimmune disease and biomarkers were measured in children and adults with congenital heart disease and either reduced or preserved thymopoiesis. Tregs were examined. Atopic or autoimmune-like symptoms and elevated anti-dsDNA antibodies were common after surgery in individuals with low thymopoiesis. Total Treg number and function were maintained but with fewer naïve Treg. TCR spectratypes were similar to other memory T cells. These data suggest that thymectomy does not reduce total Treg number but homeostasis is affected with reduced naïve Treg. Prevalence of autoimmune or atopic symptoms after surgery is not associated with total number or proportion of Tregs but appears to be due to otherwise unknown factors that may include altered Treg homeostasis.