Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset designated Th9. IRF4-deficient CD4(+) T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4(+) T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4(+) T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.
Summary
Dysregulations concerning the composition and function of regulatory T cells (Tregs-Tregs. The suppressive activity of the total Treg cell pool was diminished in both patient collectives. Hence, our findings propose that pre-eclampsia and PL are characterized by homeostatic changes in the composition of the total Treg pool with distinct Treg subsets that were accompanied by a significant decrease of its suppressive activity.
Regulatory T cells (Tregs) exert a key role in tolerance induction to the semi-allogeneic fetus. Currently, it is not known whether immunological rejection processes are involved in the induction of normal term or irresistible preterm labor. In this study, we examined whether there were differences in the percentage of the total CD4 þ CD127 low þ / À CD25 þ FoxP3 þ -Treg-cell pool, its suppressive activity and its composition with distinct Treg subsets (HLA-DR low þ -, HLA-DR high þ -, HLA-DR À -and naive CD45RA þ -Tregs) between preterm and term laboring women. We found that its percentage was decreased neither in term nor in preterm laboring women. Its suppressive activity was strongly diminished in preterm laboring women and to a lesser extent in spontaneously term laboring women. During the normal course of pregnancy, its composition changed in such a way that the percentage of naive CD45RA þ -Tregs increased while the percentage of the highly suppressive HLA-DR low þ -and HLA-DR high þ -Tregs decreased significantly until term. With the onset of spontaneous term labor this phenomenon was reversed and reached significant values postpartum. In addition, we confirmed that both the decreased percentage of HLA-DR þ -Tregs within the total Treg-cell pool and their decreased level of HLA-DR expression (depending on the percentage of HLA-DR low þ -and HLA-DR high þ -Tregs) had a reducing effect on the suppressive activity of the total Treg cell pool in preterm laboring women. However, spontaneous term delivery was associated with increasing percentages of HLA-DR þ -Tregs and increasing HLA-DR expression of this Treg subset. Therefore, it becomes apparent that the mechanisms inducing term or preterm labor may be completely different. Keywords: pregnancy; preterm labor; regulatory T cells; subsets of regulatory T cells; term labor; tolerance induction During pregnancy, the maternal immune system is continuously confronted with paternal alloantigens, which are expressed by the fetus and the placenta. The complex immunologically controlled mechanisms that prevent the rejection of the fetus are still incompletely understood. Normally, the fetus grows and develops very well with ongoing pregnancy, until the onset of spontaneous labor induces vaginal delivery of the fetus after about 38-42 weeks of gestation. Unfortunately, in about 12-13% cases in the United States and 5-9% cases in many other developed countries, pregnancy ends as a premature birth, 1 often because of the occurrence of contractions that cannot be inhibited by tocolytic treatment. Currently, it is not known whether the maternal immune system rejects the semiallogeneic fetus at term, nor do we know whether immunological rejection processes participate in the induction of irresistible preterm labor. However, studies in mouse models clearly demonstrated that immunosuppressive regulatory T cells (Tregs) are decisively involved in inducing maternal immune tolerance to the fetus. 2 Maternal CD4 þ CD25 high þ -Tregs were shown to be expanded in both allogeneic ...
For the identification of women with an increased risk of IUGR and/or preeclampsia, measurement of sHLA-G1/G5 plasma levels may be a powerful new tool in prenatal diagnostics.
SummaryPhysiological changes during normal pregnancy are characterized by an inflammatory immune response and insulin resistance. Therefore, we hypothesize that gestational diabetes mellitus (GDM) may be caused by an inappropriate adaption of the maternal immune system to pregnancy. In this study we examined the role of regulatory T cell (Treg) differentiation for the development of GDM during pregnancy. We used six-colour flow cytometric analysis to demonstrate that the total CD4 + T helper cell pool was not different in patients affected by GDM. However, the suppressive activity of the total CD4 + CD127 low+/− CD25 + Treg pool was significantly reduced in GDM patients. The composition of the total Treg pool changed in the way that its percentage of naive CD45RA + Tregs was decreased significantly in both patients with dietary-adjusted GDM and patients with insulin-dependent GDM. In contrast, the percentage of DR − -memory Tregs was increased significantly in patients with dietary-adjusted GDM, while the percentage of DR low+ and DR high+ memory Tregs was increased significantly in patients with insulin-dependent GDM. Hence, our findings propose that alterations in homeostatic parameters related to the development and function of naive and memory Tregs may cause the reduction of the suppressive capacity of the total Treg pool in GDM patients. However, as this is an exploratory analysis, the results are only suggestive and require further validation.
Recent studies show that regulatory T cells (Tregs) play an essential role in tolerance induction after organ transplantation. In order to examine whether there are differences in the composition of the total CD4+CD127low+/−FoxP3+- Treg cell pool between stable transplant patients and patients with biopsy proven rejection (BPR), we compared the percentages and the functional activity of the different Treg cell subsets (DRhigh+CD45RA−-Tregs, DRlow+CD45RA−-Tregs, DR−CD45RA−-Tregs, DR−CD45RA+-Tregs). All parameters were determined during the three different periods of time after transplantation (0–30 days, 31–1,000 days, >1,000 days). Among 156 transplant patients, 37 patients suffered from BPR. The most prominent differences between rejecting and non-rejecting patients were observed regarding the DRhigh+CD45RA−-Treg cell subset. Our data demonstrate that the suppressive activity of the total Treg pool strongly depends on the presence of these Treg cells. Their percentage within the total Treg pool strongly decreased after transplantation and remained relatively low during the first year after transplantation in all patients. Subsequently, the proportion of this Treg subset increased again in patients who accepted the transplant and reached a value of healthy non-transplanted subjects. By contrast, in patients with acute kidney rejection, the DRhigh+CD45RA−-Treg subset disappeared excessively, causing a reduction in the suppressive activity of the total Treg pool. Therefore, both the monitoring of its percentage within the total Treg pool and the monitoring of the HLA-DR MFI of the DR+CD45RA−-Treg subset may be useful tools for the prediction of graft rejection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.