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Objective CD4 + CD25 + Foxp3 + regulatory T (Treg) cell-mediated immunosuppression is an essential mechanism of rheumatoid arthritis (RA). However, little is known regarding the specific role of CD4 + CD25 − Foxp3 + Treg cells in RA. This study aimed to investigate the frequency of circulating CD4 + CD25 − Foxp3 + Treg cells and their role in RA. Methods Sixty-one untreated RA patients and 40 healthy controls (HCs) were enrolled in this study. The proportion of CD4 + CD25 − Foxp3 + T cells and CD4 + CD25 + Foxp3 + Tregs; the levels of CTLA4, GITR, Helios, and ICOS; and the production of IL-17A, IFN-γ, and IL-10 were assessed by flow cytometry. The correlation of CD4 + CD25 – Foxp3 + T cells and CD4 + CD25 + Foxp3 + Tregs with the clinical indicators was conducted by Spearman correlation analysis. Results The proportion of CD4 + CD25 – Foxp3 + T cells was elevated in RA and positively correlated with disease activity. CD4 + CD25 – Foxp3 + T cells expressed less Helios and produced more IFN-γ than conventional Tregs in RA. Additionally, the proportion of CD4 + CD25 – Foxp3 + T cells was positively correlated with DAS28 score, IgG titer, and anti-CCP titer. Conclusions These data indicate that CD4 + CD25 − Foxp3 + T cells in RA exhibit several different functional properties from conventional Tregs and are correlated with RA disease activity. Highlights The proportion of CD4 + CD25 − Foxp3 + T cells was elevated in untreated RA. CD4 + CD25 − Foxp3 + T cells expressed decreased Helios compared with Treg cells in both RA patients and HCs. CD4 + CD25 − Foxp3 + T cells produced increased IFN-γ compared with Tregs in RA patients. Elevated CD4 + CD25 − Foxp3 + T cells were positively correlated with DAS28 score, anti-IgG titer and anti-CCP titer.

The imbalance of CD4 Foxp3 T cell subsets is reportedly involved in abnormal inflammatory immune responses in patients with chronic obstructive pulmonary disease (COPD). However, the possible role of CD4 CD25 Foxp3 T cells in immune regulation in COPD remains to be investigated. In the current study, distribution and phenotypic characteristics of CD4 CD25 Foxp3 T cells from peripheral blood were determined by flow cytometry; the origin, immune function and ultimate fate of CD4 CD25 Foxp3 T cells were further explored . It was observed that circulating CD4 CD25 Foxp3 T cells were significantly increased in stable COPD patients (SCOPD) and resembled central memory or effector memory T cells. Compared with peripheral CD4 CD25 Foxp3 T cells, peripheral CD4 CD25 Foxp3 T cells showed a lower expression of Foxp3, CTLA-4, HELIOS, and TIGIT, but a higher expression of CD127 and KI-67, suggesting that CD4 CD25 Foxp3 T cells lost the expression of Tregs-associated molecules following the reduction in CD25. Unexpectedly, our study found that transforming growth factor-β1 (TGFβ1) decreased CD25 expression and played a critical role in the generation of CD4 CD25 Foxp3 T cells from CD4 CD25 Foxp3 T cells. Phenotypic analysis further revealed that both inducible and peripheral CD4 CD25 Foxp3 T cells exhibited the features of activated conventional T cells. Importantly, memory CD4 CD25 Foxp3 T cells facilitated the proliferation and differentiation of naïve CD4 T cells into Th17 cells in the presence of IL-1β, IL-6, IL-23, and TGFβ1. Finally, a fraction of CD4 CD25 Foxp3 T cells, exhibiting instability and plasticity, were converted to Th17 cells when subjected to Th17 cell-polarizing condition. Taken together, we propose that TGFβ1 is responsible for the generation of CD4 CD25 Foxp3 T cells, and these cells functionally exert an auxiliary effect on Th17 cells generation and might perpetuate chronic inflammation in COPD.

Plasmacytoid dendritic cells are the most efficient producers of type I interferons, viz. IFNα, in the body and thus have the ability to influence anti-tumor immune responses. But repression of effective intra-tumoral pDC activation is a key immuno-evasion strategy exhibited in tumors-tumor-recruited pDCs are rendered \"tolerogenic,\" characterized by deficiency in IFNα induction and ability to expand regulatory T cells . But the tumor-derived factors that drive this functional reprogramming of intra-tumoral pDCs are not established. In this study we aimed at exploring if intra-tumoral abundance of the oncometabolite lactate influences intra-tumoral pDC function. We found that lactate attenuates IFNα induction by pDCs mediated by intracellular Ca mobilization triggered by cell surface GPR81 receptor as well as directly by cytosolic import of lactate in pDCs through the cell surface monocarboxylate transporters, affecting cellular metabolism needed for effective pDC activation. We also found that lactate enhances tryptophan metabolism and kynurenine production by pDCs which contribute to induction of FoxP3 CD4 regulatory T cells, the major immunosuppressive immune cell subset in tumor microenvironment. We validated these mechanisms of lactate-driven pDC reprogramming by looking into tumor recruited pDCs isolated from patients with breast cancers as well as in a preclinical model of breast cancer in mice. Thus, we discovered a hitherto unknown link between intra-tumoral abundance of an oncometabolite resulting from metabolic adaptation in cancer cells and the pro-tumor tolerogenic function of tumor-recruited pDCs, revealing new therapeutic targets for potentiating anti-cancer immune responses.

There are conflicting data regarding the prognostic effect of microvascular density (MVD) in breast cancer and its molecular subtypes. It is thought that high levels of FOXP3 + T cells in breast cancer are associated with poor prognosis. However, data regarding FOXP3 show significant variability in the literature. In our study, we aim to measure MVD and FOXP3 + T cells in breast cancer cases and investigate their relationship with each other and their effects on breast cancer patients’ clinical and prognostic features. In our study, the results of 207 female breast cancer patients whose excisional tumoral tissue was obtained are presented. The study evaluated the findings under a light microscope using antibodies against CD34 for measuring MVD and FOXP3 for measuring FOXP3-positive T cells. CD34 ≥ 17 was categorized as high MVD, and CD34 < 17 was classified as low MVD. FOXP3 + cell count ≥ 20/mm2 was categorized as high FOXP3 positivity and < 20/mm2 as low FOXP3 positivity. The SPSS program (version 22) was used to evaluate the results statistically, and p  < 0.05 was considered significant. The median age was 54.0 (27–86) years, and the median follow-up period was 60.0 (IQR: 42.6–86.5) months. In the high MVD group, a higher progesterone receptor (PR) positivity rate was detected ( p  = 0.035). High FOXP3 positivity was significantly associated with high nuclear grade ( p  = 0.003). High FOXP3 positivity was significantly associated with PR negativity and high Ki67 values ​​( p  = 0.009, p  = 0.012, respectively). No statistically significant correlation was found between MVD elevation and FOXP3 positivity ( r  = 0.063, p  = 0.36). A weakly significant positive correlation was detected between high Ki67 and FOXP3 positivity ( r  = 0.0146, p  = 0.04). A weak inverse correlation was detected between high FOXP3 positivity and PR percentage values ​​( r =-0.182, p  = 0.01). While there was no significant difference in disease-free survival in cases with high MVD and high FOXP3 + T cells compared to groups with low levels, the results were not mature enough because the median values ​​in overall survival could not be reached. A significant correlation was found between high FOXP3 positivity and some aggressive tumor features; no effect on survival was detected. In contrast to literature data on luminal A breast cancer, high MVD in the luminal B (HER2-) subgroup was associated with a lower risk of recurrence. Our study is the first in the literature to evaluate the relationship between MVD measured using CD34 and FOXP3 positive T cells in breast cancer. Our study found no correlation between MVD and FOXP3 positivity, while literature data show significant correlations in some other cancers.

Forkhead box P3 (Foxp3) T regulatory cells are critical for maintaining self-tolerance, immune homeostasis, and regulating the immune system. We investigated interleukin-4 receptor alpha (IL-4Rα) signalling on T regulatory cells (Tregs) during ( ) infection using a mouse model on a BALB/c background, specifically with IL-4Rα knockdown in Tregs (Foxp3 IL-4Rα ). We showed an impairment of Treg responses, along with a decreased bacterial burden and diminished tissue pathology in the liver and spleen, which translated into better survival. Mechanistically, we observed an enhancement of the Th1 signature, characterised by increased expression of the T-bet transcription factor and a greater number of effector T cells producing IFN-γ, IL-2 following stimulation with heat-killed in Foxp3 IL-4Rα mice. Furthermore, CD8 T cells from Foxp3 IL-4Rα mice displayed increased cytotoxicity (Granzyme-B) with higher proliferation capacity (Ki-67), better survival (Bcl-2) with concomitant reduced apoptosis (activated caspase 3). In contrast to , Foxp3 IL-4Rα mice displayed similar bacterial burdens, lung pathology and survival during ( ) infection, despite increased T cell numbers and IFN-γ, TNF and IL-17 production. Our results demonstrated that the diminished IL-4Rα signalling on Foxp3+ T regulatory cells resulted in a loss of their functionality, leading to survival benefits in listeriosis but not in tuberculosis.

Background Gallbladder cancer (GBC), although infrequent in industrialized countries, has high incidence rates in certain world regions, being a leading cause of death among elderly Chilean women. Surgery is the only effective treatment, and a five-year survival rate of advanced-stage patients is less than 10%. Hence, exploring immunotherapy is relevant, although GBC immunogenicity is poorly understood. This study examined the relationship between the host immune response and GBC patient survival based on the presence of tumor-infiltrating lymphocytes at different disease stages. Methods Tumor tissues from 80 GBC patients were analyzed by immunohistochemistry for the presence of CD3 + , CD4 + , CD8 + , and Foxp3 + T cell populations, and the results were associated with clinical stage and patient survival. Results The majority of tumor samples showed CD3 + T cell infiltration, which correlated with better prognosis, particularly in advanced disease stages. CD8 + , but not CD4 + , T cell infiltration correlated with improved survival, particularly in advanced disease stages. Interestingly, a < 1 CD4 + /CD8 + T cell ratio was related with increased survival. Additionally, the presence of Foxp3 + T cells correlated with decreased patient survival, whereas a ≤ 1 Foxp3 + /CD8 + T cell ratio was associated with improved patient survival. Conclusions Depending on the disease stage, the presence of CD8 + and absence of Foxp3 + T cell populations in tumor tissues correlated with improved GBC patient survival, and thus represent potential markers for prognosis and management of advanced disease, and supports testing of immunotherapy.

Objectives To facilitate disease prognosis and improve precise immunotherapy of gastric cancer (GC) patients, a comprehensive study integrating immune cellular and molecular analyses on tumor tissues and peripheral blood was performed. Methods The association of GC patients’ outcomes and the immune context of their tumors was explored using multiplex immunohistochemistry (mIHC) and transcriptome profiling. Potential immune dysfunction mechanism/s in the tumors on the systemic level was further examined using mass cytometry (CyTOF) in complementary peripheral blood from selected patients. GC cohorts with mIHC and gene expression profiling data were also used as validation cohorts. Results Increased CD4+FOXP3+ T‐cell density in the GC tumor correlated with prolonged survival. Interestingly, CD4+FOXP3+ T cells had a close interaction with CD8+ T cells rather than tumor cells. High densities of CD4+FOXP3+ T cells and CD8+ T cells (High‐High) independently predicted prolonged patient survival. Furthermore, the interferon‐gamma (IFN‐γ) gene signature and PDL1 expression were up‐regulated in this group. Importantly, a subgroup of genomically stable (GS) tumors and tumors with chromosomal instability (CIN) within this High‐High group also had excellent survival. The High‐High GS/CIN tumors were coupled with increased frequencies of Tbet+CD4+ T cells and central memory CD4+ T cells in the peripheral blood. Conclusion These novel findings identify the combination of CD8+ T cells and FOXP3+CD4+ T cells as a significant prognostic marker for GC patients, which also could potentially be targeted and applied in the combination therapy with immune checkpoint blockades in precision medicine. In this work, we show an increased CD4+FOXP3+ T cell density in the tumour core correlated with prolonged survival and CD4+FOXP3+ T cells clustered with CD8+ T cells rather than tumour cells. High density of CD4+FOXP3+ T cells and CD8+ T cells (High‐High) independently predicted prolonged patient survival. These High‐High tumours were coupled with an increased IFN‐γ response, antigen presentation, DCs differentiation and PDL1 upregulation in the local tumours, as well as enrichment of Tbet+ CD4+ T cells and central memory CD4+ T cells circulating in the peripheral blood.

Background A major barrier to achieving a favorable outcome of chronic HBV infection is a dysregulated HBV-specific immune response resulting from immunosuppressive features of FOXP3 + T cells. A better definition of FOXP3 + T cells is essential for improving the prognosis of HBV infection. We aimed to investigate the role of CD4 + CXCR5 − FOXP3 + T cells with CTLA4 expression in patients with chronic HBV infection. Methods Treatment-naïve chronic HBV-infected patients, HBV-related hepatic failure, and a longitudinal cohort of chronic hepatitis B (CHB) patients with nucleos(t)ide analogue treatment were enrolled for analysis of CD4 + CXCR5 − FOXP3 + T cell responses by flow cytometry and single-cell RNA sequencing (scRNA-seq). Results ScRNA-seq revealed that circulating CD4 + CXCR5 − FOXP3 + T cells presented distinct inhibitory features compared to spleen tissue. Meanwhile, patients with treatment-naïve chronic HBV infection or with HBV-related hepatic failure showed an upregulation of immune-suppressive features (PD-1, CTLA4, GITR) on CD4 + CXCR5 − FOXP3 + T cells; in vitro analysis found HBeAg and HBcAg stimulation induced elevated levels of inhibitory molecules. Notably, the frequency of CTLA4 + CD4 + CXCR5 − FOXP3 + T cells was positively correlated with HBV DNA levels, and longitudinal analysis demonstrated a high frequency of this subset at 12 weeks of antiviral treatment predicted unfavorable outcome in CHB patients. Conclusions CTLA4 + CD4 + CXCR5 − FOXP3 + T cells are related to unfavorable outcomes in HBV-infected patients; these data indicated that alleviating CTLA4 + CD4 + CXCR5 − FOXP3 + T cells may improve the prognosis of HBV infection.

Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive polyarthritis, and abnormal T–B‐cell interactions may contribute to its pathogenesis. This study aimed to investigate the characteristics and roles of CD4+ programmed death 1 (PD‐1)+Foxp3− T cells in relation to the B‐cell response in patients with RA. Methods This study included 155 patients with RA and 36 age‐ and sex‐matched healthy controls (HCs) from the Second Hospital of Dalian Medical University in China. Flow cytometry was used to assess the proportion and properties of peripheral CD4+PD‐1+Foxp3+ T cells, including their proliferation, activation, cytokine production, and capacity to induce B‐cell differentiation. Results The proportion of CD4+PD‐1+Foxp3− T cells was increased in patients with RA compared with HCs ([10.78 ± 0.60]% vs. [5.67 ± 0.40]%, p < 0.001), and this was positively associated with the B‐cell response. Compared with CD4+PD‐1+Foxp3+ T cells, CD4+PD‐1+Foxp3− T cells from patients with RA exhibited increased expression of Ki67 ([6.52 ± 0.41]% vs. [3.87 ± 0.42]%, p < 0.01) and activation markers, produced higher levels of cytokines, and showed enhanced B‐cell differentiation. Furthermore, anti‐interleukin‐6R antagonists decreased the proportion, activation, and cytokine production of CD4+PD‐1+Foxp3− T cells in vitro. The frequency of type 2 CD4+PD‐1+Foxp3− T cells was significantly higher in patients with RA than that in HCs ([37.27 ± 1.43]% vs. [29.05 ± 1.30]%, p < 0.05). Conclusions Peripherally expanded CD4+PD‐1+Foxp3− T cells in patients with RA, which induced B‐cell hyperactivity, may be inclined toward type 2 helper T cells. Our findings revealed a novel T‐cell subset that contributes to B‐cell hyperactivity in the pathogenesis of RA. Pathologically expanded CD4+PD‐1+Foxp3− T cells of patients with rheumatoid arthritis promoted the B‐cell response in vitro. Key points Expanded CD4+PD‐1+Foxp3− T cells promoted the B‐cell response in rheumatoid arthritis (RA). RA CD4+PD‐1+Foxp3− T cells exhibited type 2 helper T‐cell characteristics. Anti‐interleukin‐6R antagonists displayed an inhibitory effect on CD4+PD‐1+Foxp3− T cells in vitro.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi-organ inflammation, linked to loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies, with a negative impact on the patients’ quality of life. Regulatory T cells have been reported as deficient in number and function in SLE patients. However, some authors also described an enrichment of this cell type. The hypothesis that certain forms of autoimmunity may result from a conversion of Treg cells into a Th17 cell phenotype has been suggested by some studies. In fact, in SLE patients’ sera, the IL-17 levels were observed as abnormally high when compared with healthy individuals. Environmental factors, such as vitamin D, that is considered a potential anti-inflammatory agent, combined with genetic and hormonal characteristics have been associated with SLE phenotype and with disease progression. The aim of this study was to evaluate the effect of vitamin D supplementation on FoxP3 expression and IL-17A-producing T cells, through FoxP3 + /IL-17A ratio. Additionally, disease evolution, serum vitamin D levels, serum autoantibodies levels and calcium metabolism (to assure safety) were also studied. We assessed 24 phenotypically well-characterized SLE patients. All patients were screened before vitamin D supplementation and 3 and 6 months after the beginning of this treatment. Peripheral blood lymphocyte’s subsets were analysed by flow cytometry. Serum 25(OH)D levels significantly increased under vitamin D supplementation ( p  = 0.001). The FoxP3 + /IL-17A ratio in SLE patients after 6 months of vitamin D supplementation was higher than that in the baseline ( p  < 0.001). In conclusion, this study demonstrated that vitamin D supplementation provided favourable, immunological and clinical impact on SLE.