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To investigate the effects of everolimus, a mechanistic/mammalian target of rapamycin (mTOR) inhibitor, on tumor growth and immune response in a mouse model of breast cancer. Human hormone receptor-positive (HR+)/human epidermal growth receptor 2-negative (HER2-) MC4-L2 cell line was used to establish a mouse model of breast cancer. The inhibitory effects of high (10 mg/kg) and low (5 mg/kg) doses of everolimus were investigated on tumor growth. Additionally, the frequency of CD4+Foxp3+ regulatory T cells (Tregs), CD8+Foxp3+ Tregs, and CD4+ and CD8+ T cells expressing cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) was explored by flow cytometry in bone marrow, lymph nodes, and spleen. Our results showed that both 10 mg/kg and 5 mg/kg doses of everolimus efficiently inhibited tumor growth, resulting in reduced breast tumor volume. In addition, it was revealed that everolimus-treated mice induced a higher frequency of CD4+Foxp3+ Tregs, CD8+Foxp3+ Tregs, and CD4+Foxp3+CTLA-4+ Tregs as well as CD4+ and CD8+ T cells expressing CTLA-4 in their bone marrow, lymph nodes, and spleen compared with standard control (vehicle-treated) in a dose-dependent manner. Furthermore, we found that everolimus treatment with 10 mg/kg and 5 mg/kg increased the frequency of Helios+Foxp3+ Tregs in the bone marrow of treated mice compared with the control group. Our results indicate that treatment with everolimus not only inhibits tumor growth but also exerts an immunomodulatory effect by inducing Tregs in the lymphoid organs of breast cancer-bearing mice. The combination of therapy with other anti-cancer agents may negate immune suppression and improve the efficacy of mTOR-targeted breast cancer therapy. [ABSTRACT FROM AUTHOR]

Objectives: Immunological tolerance is mediated by CD4+CD25+ regulatory T (Treg) cells. Studies have shown that thymic and peripheral generations of Treg cells depend on the CD28 signaling pathway. T helper 17 (Th17) cells are involved in the pathophysiology of various inflammatory diseases. Cytokines, such as interleukin (IL)-6 and TGF-β, regulate the reciprocal development of Th17 and Treg cells. In CD4+ T cells, signal transducer and activator of transcription 3 (STAT3) play a critical role in the induction of Th17 cell differentiation and inhibition of Treg cell development. Results: In this study, we investigated the STAT3 methylation and gene expression status in patients with MS. Our study demonstrated that the level of STAT3 methylation decreased in relapsing–remitting MS patient compared to control groups, which the decreases were statistically significant. STAT3 gene expression increased in patient group relative to healthy one, and the increases were found to be statistically significant. According to our findings, it can be suggested that DNA hypermethylation of STAT3 affects the gene expression. In addition, there is a strong and significant negative correlation between the methylation status and mRNA level of STAT3. [ABSTRACT FROM AUTHOR]

Summary: There is ongoing debate on how B cells contribute to the pathogenesis of multiple sclerosis (MS). The success of B‐cell targeting therapies in MS highlighted the role of B cells, particularly the antibody‐independent functions of these cells such as antigen presentation to T cells and modulation of the function of T cells and myeloid cells by secreting pathogenic and/or protective cytokines in the central nervous system. Here, we discuss the role of different antibody‐dependent and antibody‐independent functions of B cells in MS disease activity and progression proposing new therapeutic strategies for the optimization of B‐cell targeting treatments. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) is a member of the evolutionary phosphatidylinositol kinase‐related kinases (PIKKs). mTOR plays a pivotal role in the regulation of diverse aspects of cellular physiology such as body metabolism, cell growth, protein synthesis, cell size, autophagy, and cell differentiation. Immunologically, mTOR has a fundamental part in controlling and shaping diverse functions of innate and adaptive immune cells, in particular, T‐cell subsets differentiation, survival, and metabolic reprogramming to ultimately regulate the fate of diverse immune cell types. Researchers report that rapamycin, a selective mTOR inhibitor, and immunosuppressive agent, has surprising immunostimulatory effects on inducing both quantitative and qualitative aspects of virus‐specific memory CD8+ T‐cells differentiation and homeostasis in a T‐cell‐intrinsic manner. The mTOR signaling pathway also plays a critical role in dictating the outcome of regulatory T cells (Treg), T helper 17 (Th17) cells, and natural killer (NK) cells proliferation and maturation, as well as the effector functions and cytotoxic properties of NK cells. Manipulation of mTOR activity is a critical therapeutic approach for pharmacological agents that seek to inhibit mTOR. This approach should enhance specific memory CD8 + T‐cells responses and induce fully functional effector properties of NK cells to provoke their antitumor and antiviral activities. [ABSTRACT FROM AUTHOR]

CD11c is a member of the β2‐integrin family typically used to define myeloid dendritic cells (DCs). Recent reports identify CD11c‐expressing CD8+ T cells as a new subset of CD8+ regulatory T cells (Treg). Evidence exists that CD11c+CD8+ T cells may exert their effector or regulatory functions under different conditions. To date, no studies have addressed the frequency of CD11c+ T cells in cancer. Limited evidence exists in terms of expression of immune‐checkpoint receptors, programmed cell death protein 1 (PD‐1) and T‐lymphocyte‐associated antigen 4 (CTLA‐4), as well as forkhead box P3 (Foxp3) in mouse lymphoid organs. Here, we have assessed CD11c+CD8+ and CD11c+CD4+ T cells, Foxp3, PD‐1, and CTLA‐4 expressing CD4+ T cells and CD8+ T cells in different tissues from three groups of male BALB/c mice—young, mature, and those with colorectal cancer (CRC). Analysis of CD3+CD11c+ T cells in the bone marrow (BM), spleen, and lymph nodes (LN) in each group showed a higher percentage of CD3+CD11c+ T cells in the BM from all groups and in the lymphoid organs of the cancer group compared with the young and mature groups. CD4low and CD4high cell fractions in mice BM have different expression patterns for Foxp3 and CTLA‐4. We have observed a higher frequency of CD8+PD‐1+ T cells in the BM, spleen, and LN of CRC mice compared with normal mice. T‐cell exhaustion is associated with inhibitory receptor PD‐1. According to the regulatory roles of CD11c expression in CD8+ T cells, we have proposed that the elevated percentage of CD11c, Foxp3, CTLA‐4, and PD‐1 expressing T cells were associated with immune response dysregulation in CRC. Recent reports identify CD11c‐expressing CD8+ T cells as a new subset of CD8+ regulatory T cells. Analysis of CD3+CD11c+ T cells in the bone marrow (BM), spleen, and lymph nodes (LN) in each group showed a higher percentage of CD3+CD11c+ T cells in the BM from all groups and in the lymphoid organs of the cancer group compared with the young and mature groups. We have observed a higher frequency of CD8+PD‐1+ T cells, T‐lymphocyte‐associated antigen 4 and forkhead box P3 expression in the BM, spleen, and LN of colorectal cancer mice compared with normal mice. [ABSTRACT FROM AUTHOR]

In the current study, we aimed to identify nanocurcumin effects on microRNAs (miRNAs) in the peripheral blood of patients with relapsing‐remitting multiple sclerosis (RRMS). We intended to investigate the expression pattern of these miRNAs in experimental settings in vivo. The expression levels of the selected 27 miRNAs known to be involved in the regulation of immune responses were analyzed in 50 RRMS patients and 35 healthy controls. The miRNA expression profiles were investigated by quantitative PCR (qPCR) at baseline and after 6 months of nanocurcumin therapy. Our data revealed that the expression of a number of microRNAs including miR‐16, miR‐17‐92, miR‐27, miR‐29b, miR‐126, miR‐128, miR‐132, miR‐155, miR‐326, miR‐550, miR‐15a, miR‐19b, miR‐106b, miR‐320a, miR‐363, miR‐31, miR‐150, and miR‐340 is regulated by nanocurcumin. The results of the current work indicate that nanocurcumin is able to restore the expression pattern of dysregulated miRNAs in MS patients. We discovered that some miRNAs are deregulated in untreated patients compared with healthy controls and nanocurcumin‐treated patients. This is a new finding that might represent the potential contribution of these miRNAs to MS pathogenesis. Taken together, these data provide novel insights into miRNA‐dependent regulation of the function of B and T cells in MS disease and enrich our understanding of the effects mediated by a therapeutic approach that targets B and T cells. [ABSTRACT FROM AUTHOR]

CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in peripheral immunity. Immune responses are main elements in the pathogenesis of ischemic stroke (IS). The contribution of Th17 cells in IS patients has not been proved, and whether the balance of Treg/Th17 cells is changed in IS patients remains unidentified. In the present study, we studied Th17 and Treg cell frequency, cytokine secretion, expression of transcription factors, and microRNAs related to Th17 and Treg cells differentiation, which is compared between IS patients and control group. Thirty patients with IS and 30 individuals as control group were enrolled in this study. The frequency of Th17 and Treg lymphocytes, the expression of transcription factors and microRNAs related to these cells, and the serum levels of associated cytokines were assessed by flow cytometry, real-time PCR, and ELISA, respectively. A significant reduction in proportion of peripheral Treg cell frequency and the levels of TGF-β and FOXP3 expression were observed in patients with IS compared with controls, while the proportions of Th17 were increased dramatically, and these effects were along with increases in the levels of IL-17A and RORγt expression in IS patients. The levels of mir-326 and mir-106b-25 expression were increased in patients with IS. These studies suggest that the increase in proportion of Th17 cells and decrease in Treg cells might contribute to the pathogenesis of IS. Manipulating the balance between Tregs and Th17 cells might be helpful for the treatment of IS. [ABSTRACT FROM AUTHOR]

Background and aim: The etiology of Oral Lichen Planus (OLP) is not known, autoreactive T lymphocytes may being involved in the pathogenesis of OLP. We aimed in this study to investigate the relationship between Interleukin-8 (IL-8) and Interleukin-1B (IL-1B) levels and disease activity in the patients suffering from OLP. Materials and methods: This descriptive analytical study included 56 patients with OLP and 50 healthy control individuals. Blood samples were obtained from both subjects. Serum IL-8 and IL-1B was determined by ELISA kit. Results: The Level of IL-8 (168.23 ± 33.2) and IL-1B (174.18 ± 23.2) were higher in OLP patients in comparison to healthy control group, respectively (P=0.004 and P < 0.001). Conclusions: The high levels of IL-1B and IL-8 in OLP patients indicate the role of immunity in the development of the disease. [ABSTRACT FROM AUTHOR]

Background and aims Multiple sclerosis (MS) is an inflammatory condition of the central nervous system, with genetic and environmental factors having a role in its etiology. The condition is characterized by demyelination, acute inflammation, and chronic and acute lesions in the central nervous system. Human and experimental studies have shown that T-helper cells, and pro-inflammatory cytokines have a major role in the pathogenesis of MS. Recent researches have shown that IL-17 secreting T (Th17) cells have a role in inflammation and demyelination of the central nervous system. In the present study, the role of Interleukin-17A (IL-17A) and Interleukin-17F (IL-17F) in the immunopathogenesis and follow-up of the MS disease was evaluated. Materials and methods Thirty-five relapsing remitting (RR) form of MS patients were included in the present study. Blood samples were taken from 35 MS patients and 35 healthy individuals as controls. Enzyme-Linked Immunosorbent Assay (ELISA) was used to determine IL-17A and IL-17F serum levels. Results A statistically significant increase was noted in the serum levels of IL-17A and IL-17F in MS patients compared to the controls ( P < 0.001). There was a significant positive correlation of IL-17F serum levels with the number of relapses (rs = 0.717, P < 0.001). However, there was no significant relationship between the serum levels of these cytokines and Expanded Standard Disability Stated Scale (EDSS) and disease Progression Index (PI). Conclusion The data of the present study revealed a significant increase in the serum levels of IL-17A and IL-17F in MS patients compared with healthy controls and a significant positive correlation of IL-17F serum levels with the number of relapses. It appears that increased serum levels of IL-17 and especially IL-17F may lead to a raised risk of MS. [ABSTRACT FROM AUTHOR]

• COVID-19 is a novel viral infection that has been a worldwide health threat as currently infected more than eighty million people in the world. • Reduced number and function of T cells were observed in ICU-admitted COVID-19 patients may have a correlation with the severity of the disease. • Hypercholesterolemia and hyperlipidemia could be important prognostic factors to determine the severity of the SARS-CoV-2 infection. Coronavirus disease 2019 (COVID-19) is a novel viral infection threatening worldwide health as currently there exists no effective treatment strategy and vaccination programs are not publicly available yet. T lymphocytes play an important role in antiviral defenses. However, T cell frequency and functionality may be affected during the disease. Total blood samples were collected from patients with mild and severe COVID-19, and the total lymphocyte number, as well as CD4+ and CD8 + T cells were assessed using flowcytometry. Besides, the expression of exhausted T cell markers was evaluated. The levels of proinflammatory cytokines were also investigated in the serum of all patients using enzyme-linked immunesorbent assay (ELISA). Finally, the obtained results were analyzed along with laboratory serological reports. COVID-19 patients showed lymphopenia and reduced CD4+ and CD8 + T cells, as well as high percentage of PD-1 expression by T cells, especially in severe cases. Serum secretion of TNF-α, IL-1β, and IL-2 receptor (IL-2R) were remarkably increased in patients with severe symptoms, as compared with healthy controls. Moreover, high levels of triglyceride (TG) and low density lipoprotein cholesterol (LDL-C), were correlated with the severity of the disease. Reduced number and function of T cells were observed in COVID-19 patients, especially in severe patients. Meanwhile, the secretion of proinflammatory cytokines was increased as the disease developed. High level of serum IL-2R was also considered as a sign of lymphopenia. Additionally, hypercholesterolemia and hyperlipidemia could be important prognostic factors in determining the severity of the infection. [ABSTRACT FROM AUTHOR]

• IL-21 is a proinflammatory cytokine produced by Th-17 and Tfh cells. • IL-21 mRNA level and serum level were significantly increased in MS patients. • IL-21 mRNA, serum level and its promoter methylation are correlated with MS disease severity and progression. • IL-21-producing T cell subpopulations percentages are positively correlated with MS severity and progression. Multiple sclerosis is a common neuroinflammatory disease of the central nervous system causing nervous system defects and severe physical disability. IL-21 is a proinflammatory cytokine produced mainly by Th-17 and Tfh cells which its exact role in MS was not yet clearly understood. In the present study we aimed to investigate the possible correlation of IL-21 gene expression, methylation, and its serum levels with MS severity and progression. The results showed that IL-21 mRNA level and serum level were significantly increased in patient group compared with control group (p = 0.02 and p < 0.0001 respectively). Moreover, we found a strong positive correlation between IL-21 mRNA levels and EDSS scores (r = 0.637, P < 0.0001), IL-21 mRNA levels and Progression Index (r = 0.540, P < 0.0001), IL-21 serum levels and EDSS scores (r = 0.617, P < 0.0001), and IL-21 serum levels and Progression Index (r = 0.527, P < 0.0001) in MS patients. Additionally, we found that the methylation level of IL-21 promoter region was decreased in patient group compared with the control group (p < 0.0001). We also found that methylation level of IL-21 gene promoter is negatively correlated with the IL-21 mRNA level (r = −0.263, p = 0.02), serum level (r = −0.249, p = 0.03), EDSS scores (r = −0.276, p = 0.01) and Progression Index (r = −0.430, p = 0.0001). Data showed that the increased percentages of IL-21-producing Tfh-like, Th-17 and Th1 cells in patients are positively correlated with MS severity and progression. The results of our study suggest a pro-inflammatory and booster role for IL-21 in the MS pathogenesis and progression. [ABSTRACT FROM AUTHOR]

Highlights • Foxp3-expressing regulatory T cells play a crucial role in preventing autoimmunity. • A significant association of Foxp3 −3279 A allele with augmented risk of RA in Iranian patients compared to wild-type allele. • RA patients with AA genotype had a significant reduction in frequency of Tregs compared to patients with CC and CA genotypes. • TGF-β and IL-10 significantly diminished in patients with AA genotype compared to patients with CA and CC genotypes. Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease that mainly affects joints and characterized by chronic joint inflammation and infiltration of various immune cells in the synovium. Forkhead box P3 (Foxp3)-expressing regulatory T cells (Tregs) play a crucial role in preventing autoimmunity and undesirable T cell responses. However, there are controversial reports regarding the defective function or frequency of these cells in various studies, which may be in part related to different polymorphisms of FoxP3 and influence of ethnicity on these differences. Therefore, the main subject of this study was to evaluate the association of Foxp3 gene polymorphism and Treg frequency in Iranian patients with RA. Accordingly, 240 RA patients diagnosed according to American college of rheumatology 2010 criteria and 240 normal subjects were recruited for this study. Genomic DNA was genotyped for –3279 C/A Foxp3 gene SNP using the PCR-RFLP. The frequency of Tregs and serum levels of interleukin (IL)-10, transforming growth factor (TGF)-β, anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were determined by flow cytometry and ELISA methods, respectively. The results showed a significant association of Foxp3 −3279 A allele with augmented risk of RA in Iranian patients compared to wild-type allele. While the frequencies of CA and AA genotypes were significantly higher in patients, RA patients with AA genotype had a significant lower frequency of Tregs compared to patients with CC and CA genotypes. Consistently, TGF-β and IL-10 significantly diminished in patients with AA genotype compared to patients with CA and CC genotypes. Our findings indicated that the AA genotype of Foxp3 in RA patients is associated with downregulation of Tregs and susceptibility to RA in the Iranian population. [ABSTRACT FROM AUTHOR]

Corrigendum to "IL-21 and IL-21-producing T cells are involved in multiple sclerosis severity and progression" [Immunol. Lett. [Extracted from the article]

• We present recent advances in CTLA-4 in regulating T-cell tolerance and autoimmunity. • The structure and expression of CTLA-4, its mediated signaling and role in autoimmunity reviewed. • Modulation of CTLA-4 function is a promising strategy for immunotherapy of autoimmune diseases. CD28 and CTLA-4 are both important stimulatory receptors for the regulation of T cell activation. Because receptors share common ligands, B7.1 and B7.2, the expression and biological function of CTLA-4 is important for the negative regulation of T cell responses. Therefore, elimination of CTLA-4 can result in the breakdown of immune tolerance and the development of several diseases such as autoimmunity. Inhibitory signals of CTLA-4 suppress T cell responses and protect against autoimmune diseases in many ways. In this review, we summarize the structure, expression and signaling pathway of CTLA-4. We also highlight how CTLA-4 defends against potentially self-reactive T cells. Finally, we discuss how the CTLA-4 regulates a number of autoimmune diseases that indicate manipulation of this inhibitory molecule is a promise as a strategy for the immunotherapy of autoimmune diseases. [ABSTRACT FROM AUTHOR]