FoxP3 T cells and the pathophysiologic effects of brain death and warm ischemia in donor kidneys

Background and objectives Forkhead box P3 regulatory T cells control inflammatory responses, but it remains unclear whether they inhibit brain death-initiated inflammation and tissue injury in deceased kidney donors. Design, setting, participants, & measurement To study the actions of regulatory T cells at various stages of the donation and transplantation procedure, forkhead box P3, regulatory and inflammatory cytokine expression, and tissue injury markers were determined in time 0 kidney biopsies from deceased and living donors. Additionally, the interaction between forkhead box P3+ T cells and kidney injury molecule-1 by activated primary tubular epithelial cells was studied. Results After cold storage, the deceased donor kidneys expressed the higher mRNA levels of kidney injury molecule-1 and CD3ε. In these samples, the inflammatory cytokines IL-8 and IFN-γ and markers associated with regulation (forkhead box P3, TGF-β, and IL-10) were highly expressed compared with living donor kidneys. Correlations were found between mRNA expression levels of forkhead box P3 and kidney injury molecule-1 and forkhead box P3 and IFN-γ. Immunohistochemical analysis confirmed the presence of forkhead box P3+ T cells in donor kidneys. Renal function (analyzed by serum creatinine levels) at the first week posttransplantation correlated with kidney injury molecule-1 and forkhead box P3 mRNA levels. In vitro studies showed that kidney injury molecule-1 expression by primary tubular epithelial cells was 63% (mean) lower when cocultured with regulatory T cells compared with control T cells. Conclusions These results show that donor forkhead box P3+ T cells infiltrate the deceased donor kidney, where they may control inflammatory and injury responses

Forkhead box P3 gene expression and chromosomal analysis in a sample of Iraqi patients with multiple sclerosis

Background: Multiple Sclerosis disease is a demyelination process which interferes with the neuronal signal transmission, thus leading to different cognitive and physical dysfunctions like optic neuritis, motor, sensory and coordination problems. Recently many researches have been directed toward studying the relation between some genes and multiple sclerosis. Among the important genes to be studied in multiple sclerosis is the forkhead box P3 gene expression. Objectives: The aims of the present work were to study the expression of forkhead box P3 gene by real time polymerase chain reaction, and to perform chromosomal analysis on the multiple sclerosis patients peripheral blood lymphocytes. Patients and methods: A case-control study was performed using real time polymerase chain reaction technique to measure the relative expression of forkhead box P3 gene in peripheral blood leukocytes of 25 newly diagnosed untreated multiple sclerosis patients and comparing them with that of 25 apparently healthy controls, in addition to performing chromosomal analysis on multiple sclerosis patients peripheral blood lymphocytes. Results: Significant down-regulation in forkhead box P3 gene was detected in multiple sclerosis patients in comparison to controls. Chromosomal analysis that was performed for multiple sclerosis patients revealed normal results. Conclusion: Multiple sclerosis is associated with significant change in forkhead box P3 gene expression that can be measured by real time polymerase chain reaction technique. Furthermore, multiple sclerosis is not associated with gross chromosomal abnormalities

Forkhead box P3: the peacekeeper of the immune system.

Ten years ago Forkhead box P3 (FOXP3) was discovered as master gene driving CD4(+)CD25(+) T cell regulatory (Treg) function. Since then, several layers of complexity have emerged in the regulation of its expression and function, which is not only exerted in Treg cells. While the mechanisms leading to the highly selective expression of FOXP3 in thymus-derived Treg cells still remain to be elucidated, we review here the current knowledge on the role of FOXP3 in the development of Treg cells and the direct and indirect consequences of FOXP3 mutations on multiple arms of the immune response. Finally, we summarize the newly acquired knowledge on the epigenetic regulation of FOXP3, still largely undefined in human cells

Pathologic significance of immunoglobulin G4-positive plasma cells in extrahepatic cholangiocarcinoma

Immunoglobulin G4-related sclerosing cholangitis is histologically characterized by the infiltration of immunoglobulin G4-positive plasma cells and sclerosing change. Moreover, several cases of carcinoma accompanied by immunoglobulin G4-positive cells in tissue and increased serum immunoglobulin G4 levels have been reported, but the association between cancer-associated immunity and an immunoglobulin G4 reaction is still unclear. In this study, we examined the infiltration of immunoglobulin G4-positive cells in extrahepatic cholangiocarcinoma and the pathologic significance of the immunoglobulin G4 reaction found in cancer tissues in terms of the evasion of immune surveillance by regulatory T cells. Immunohistochemistry for immunoglobulin G4, forkhead box P3, CD4, and CD8 was performed using 68 surgical specimens from patients with extrahepatic cholangiocarcinoma, and positive cells were investigated, particularly within and around cancerous tissues. Consequently, although immunoglobulin G4+ cells were few (average, <10 cells/high-power field) in most cases, 10 or more and 50 or more cells were found in 37% and 6% of cases, respectively. Immunoglobulin G4+ cells were predominantly found in the invasive front of carcinoma tissue. In the cases with 10 or more immunoglobulin G4+ cells, forkhead box P3+ regulatory T cells were also distinguishable, and a positive correlation was found between the forkhead box P3+/CD4+ ratio and immunoglobulin G4+ cell count, but few CD8+ cells invaded cancer cells (<10 cells). In conclusion, extrahepatic cholangiocarcinomas are often accompanied by the significant infiltration of immunoglobulin G4+ cells, and the immunoglobulin G4 reaction showed a positive and negative correlation with forkhead box P3+ and CD8+ cells, respectively, suggesting the evasion of immune surveillance associated with CD8+ cytotoxic T cells via the regulatory function of forkhead box P3+ regulatory T cells. © 2012 Elsevier Inc. All rights reserved

Expansion of CD25-Negative Forkhead Box P3-Positive T Cells during HIV and Mycobacterium tuberculosis Infection

Tuberculosis (TB) and HIV alter the immune system, and coinfected (HIV-TB) individuals usually present deregulations of T-lymphocytic immune response. We previously observed an increased frequency of “unconventional” CD4+CD25−FoxP3+ Treg (uTreg) population during HIV-TB disease. Therefore, we aimed to explore the phenotype and function of uTreg and conventional CD4+CD25+FoxP3+ Treg subsets (cTreg) in this context. We evaluated the expression of CD39, programmed cell death protein 1 (PD1), glucocorticoid-induced tumor necrosis factor receptor (GITR), and the effector/memory distribution by flow cytometry in cTreg and uTreg. Also, IL-10, TGF-β, IFN-γ production, and the suppressor capacity of uTregs were analyzed in cocultures with effector lymphocytes and compared with the effect of regulatory T cells (Tregs). We found diminished expression of CD39 and higher levels of PD1 on uTreg compared to cTreg in both HIV-TB and healthy donors (HD). In addition, uTreg and cTreg showed differences in maturation status in both HIV-TB and HD groups, due to the expansion of effector memory uTregs. Interestingly, both HIV-TB and HD showed a pronounced production of IFN-γ in uTreg population, though no significant differences were observed for IL-10 and TGF-β production between uTreg and cTreg. Moreover, IFN-γ+ cells were restricted to the CD39− uTreg population. Finally, when the suppressor capacity was evaluated, both uTreg and cTreg inhibited polyclonal T cell-proliferation and IFN-γ production in a similar extent. These findings suggest that uTregs, which are expanded during HIV-TB coinfection, exert regulatory functions in a similar way to cTregs despite an altered surface expression of Treg characteristic markers and differences in cytokine production.Fil: Angerami, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Suárez, Guadalupe Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Vecchione, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Laufer, Natalia Lorna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Ameri, Diego. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; ArgentinaFil: Ben, Graciela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; ArgentinaFil: Perez, Hector. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos ; ArgentinaFil: Sued, Omar Gustavo. Fundación Huésped; ArgentinaFil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Quiroga, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Forkhead Box P3 Methylation and Expression in Men with Obstructive Sleep Apnea

BACKGROUND: Epigenetic changes in obstructive sleep apnea (OSA) have been proposed as a mechanism for end-organ vulnerability. In children with OSA, Forkhead Box P3 (FOXP3) DNA methylation were associated with inflammatory biomarkers; however, the methylation pattern and its effect in the expression of this gene have not been tested in adults with OSA. METHODS: Plasma samples from subjects without comorbid conditions other than OSA were analyzed (the Epigenetics Status and Subclinical Atherosclerosis in Obstructive Sleep Apnea (EPIOSA) Study: NCT02131610). In 16 patients with severe OSA (Apnea-Hypopnea Index-AHI- > 30 events/h) and seven matched controls (AHI 10) and 31 controls, we quantified FOXP3 protein expression by ELISA and gene expression by quantitative real-time PCR. C-reactive protein (CRP) and plasma Treg cells were also evaluated. RESULTS: Neither the levels of the promoter nor the TSDR demethylated region were different between controls and patients with OSA, whether they were grouped by normal or high CRP. FOXP3 protein and mRNA expression did not differ between groups. CONCLUSIONS: FOXP3 methylation or its expression is not altered in adults with OSA, whatever their inflammatory status

The dual role of the X-linked FoxP3 gene in human cancers

The FoxP3 (forkhead box P3) gene is an X-linked gene that is submitted to inactivation. It is an essential transcription factor in CD4(+)CD25(+)FoxP3 regulatory T cells, which are therapeutic targets in disseminated cutaneous melanoma. Moreover, FoxP3 is an important tumor suppressor gene in carcinomas and has putative cancer suppressor gene function in cutaneous melanoma as well. Therefore understanding the structure and function of the FoxP3 gene is crucial to gaining insight into the biology of melanoma to better develop immunotherapeutics and future therapeutic strategies

Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring

Allergoid–mannan conjugates are novel vaccines for allergen-specific immunotherapy being currently assayed in phase 2 clinical trials. Allergoid–mannan conjugates target dendritic cells (DCs) and generate functional forkhead box P3 (FOXP3)-positive Treg cells, but their capacity to reprogram monocyte differentiation remains unknown