OBJECTIVE: To measure regulatory T cell (Treg) levels in the peripheral blood of children with juvenile idiopathic arthritis (JIA) and analyse the association of this measure with disease activity, quality of life, adjustment of treatment, and hospitalisation.
METHODS: We conducted a two-phase study (cross-sectional and prospective), including consecutive children with a JIA diagnosis according to ILAR criteria. Our independent variables were Tregs, Th1, Th2, and cytokines in peripheral blood, and our dependent variables in the cross-sectional phase were arthritis category, JIA activity, and patient-reported outcomes. To test associations, we used Spearman\'s correlation coefficient and the Mann-Whitney U test. In the prospective phase, we explored the probability of treatment adjustment and hospitalisation for JIA during follow-up according to Tregs levels at baseline, using Cox proportional regression.
RESULTS: Our sample included 87 participants (median age 11 years, 63.2% girls). Tregs were not associated with most variables of interest. However, we found that higher Tregs concentration was associated with lower erythrocyte sedimentation rate (ESR) and better subjective disease status and course, while higher IL-10 and TGF-β levels were associated with lower ESR, less pain, and better subjective disease status We found no association between Tregs and treatment adjustments or hospitalisation.
CONCLUSIONS: Higher baseline Treg levels in the peripheral blood of children with JIA may be associated with reduced disease activity and better quality of life, though were not informative on the inflammatory progression on the follow-up.

OBJECTIVE: Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC.
METHODS: Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1β levels in human and mouse serum were assessed.
RESULTS: Interleukin-1β levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1β levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1-/-) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1β concentration. IL-1R1-/- mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver.
CONCLUSIONS: Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.

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PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.

Endometriosis is a benign disease of the female reproductive tract, characterized by the process of chronic inflammation and alterations in immune response. It is estimated to affect 2-19% of women in the general population and is commonly associated with symptoms of chronic pelvic pain and infertility. Regulatory T cells (Treg) are a subpopulation of T lymphocytes that are potent suppressors of inflammatory immune response, essential in preventing destructive immunity in all tissues. In endometriosis, several studies have investigated the possible role of Treg cells in the development of the disease. Most studies to date are heterogeneous in methodology and are based on a small number of cases, which means that it is impossible to define their exact role at present. Based on current knowledge, it seems that disturbed Treg homeostasis, leading to increased systemic and local inflammation within ectopic and eutopic endometrium, is present in women who eventually develop endometriosis. It is also evident that different subsets of human Treg cells have different roles in suppressing the immune response. Recent studies in patients with endometriosis have investigated naive/resting FOXP3lowCD45RA+ Treg cells, which upon T cell receptor stimulation, differentiate into activated/effector FOXP3highCD45RA- Treg cells, characterized by a strong immunosuppressive activity. In addition, critical factors controlling expression of Treg/effector genes, including reactive oxygen species and heme-responsive master transcription factor BACH2, were found to be upregulated in endometriotic lesions. As shown recently for cancer microenvironments, microbial inflammation may also contribute to the local composition of FOXP3+ subpopulations in endometriotic lesions. Furthermore, cytokines, such as IL-7, which control the homeostasis of Treg subsets through the tyrosine phosphorylation STAT5 signalling pathway, have also been shown to be dysregulated. To better understand the role of Treg in the development of endometriosis, future studies should use clear definitions of Tregs along with specific characterization of the non-Treg (FOXP3lowCD45RA-) fraction, which itself is a mixture of follicular Tregs and cells producing inflammatory cytokines.

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established. Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients. Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

Tamoxifen (TAM) is widely utilized in the prevention and treatment of human breast cancer and has demonstrated the potential to modulate the immune response. It has been proposed as a therapeutic tool for immune-mediated diseases. TAM has been investigated as a possible treatment for asthma-like conditions in horses, revealing specific impacts on the innate immune system. While the effects of TAM on equine neutrophils are well-documented, its influence on lymphocytes and the modulation of the immune response polarization remains unclear. This in vitro study employed peripheral blood mononuclear cells (PBMC) from healthy horses, exposing them to varying concentrations of the TAM and assessing the expression of genes involved in the polarization of the immune response (TBX21, IFNG, GATA3, IL4, IL10, FOXP3, and CTLA4) in PBMC stimulated or not with PMA/ionomycin. Additionally, the effect of TAM over the proportion of regulatory T cells (Treg) was also assessed. TAM did not significantly affect the expression of these genes and Treg at low concentrations. However, at the highest concentration, there was an impact on the expression of GATA3, IL4, IL10, and CTLA4 genes. These alterations in genes associated with a Th2 and regulatory response coincided with a noteworthy increase in drug-associated cytotoxicity but only at concentrations far beyond those achieved in pharmacological therapy. These findings suggest that the effects of TAM, as described in preclinical studies on asthmatic horses, may not be attributed to the modification of the adaptive response.

CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.

Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and is associated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.

UNASSIGNED: Forkhead box P3 (FoxP3) transcription factor plays critical roles in controlling immune responses and cancer progression in different cancers. FoxP3 expression within the tumor microenvironment (TME) may influence clinical outcomes negatively or positively, and it could play dual roles in cancer, either by promoting or inhibiting tumor development and progression. Some studies reported that high levels of FoxP3 could be associated with tumor progression and worse prognosis, while others reported contradictory results.
UNASSIGNED: In this special report, we present a brief account on the role and function of FoxP3 in the TME, and its contribution to the clinical outcomes of cancer patients. Importantly, we give insights on the potential factors that could contribute to different clinical outcomes in cancer patients.
UNASSIGNED: Different studies showed that FoxP3 expression can be associated with bad prognoses in cancer patients. However, FoxP3 could have opposing roles by enhancing cancer progression or regression. Location and expression of FoxP3 in T cells or tumor cells can have different impacts on cancer prognoses. Different factors should be considered to establish FoxP3 as a more robust prognostic biomarker and a potential therapeutic target for enhancing anti-tumor immunity and improving clinical outcomes of cancer patients.