Epithelial barrier biology: good fences make good neighbours.

The external surfaces of the body, such as the skin and the gastrointestinal mucosal membrane, are an important line of defence preventing the invasion of microorganisms and their products. Mucosal immune cells, especially intraepithelial lymphocytes, are involved in maintaining the integrity of these epithelial barriers. They contribute towards the tolerance to commensal organisms, which occupy these same sites, and to the immune responses against harmful organisms and their products. The composition of the microbiota is influenced by immune cells as well as external environmental factors, especially the use of antibiotics and diet. There is an increasing appreciation that the microbiota affects systemic immune responses in addition to local immunity. Failure to control the occupancy by microorganisms may result in the disruption of the delicate homeostasis between beneficial and harmful microorganisms and contribute to inflammatory pathologies. This review will discuss some of our current understanding of the impact of immune cells and diet on the microbiota.

IL-23R and TCR signaling drives the generation of neonatal Vgamma9Vdelta2 T cells expressing high levels of cytotoxic mediators and producing IFN-gamma and IL-17.

The immune system in early life is regarded as immature. However, the IL-12 family member IL-23 is highly produced upon TLR stimulation by neonatal DCs. Human adult Vγ9Vδ2 T cells can be stimulated specifically via their TCR by phosphoantigens (as the pathogen-derived HMB-PP) or agents and infections that lead to their endogenous accumulation (as the aminobisphosphonate zoledronate). As increasing evidence indicates that γδ T cells are especially important in early life, we investigated the effect of IL-23 on neonatal Vγ9Vδ2 T cells stimulated via their TCR. Zoledronate induced clear proliferation and IFN-γ production in neonatal Vγ9Vδ2 T cells. In contrast, HMB-PP did not elicit a distinct response unless at high concentrations. Addition of IL-23 to zoledronate enhanced the expression of IFN-γ and generated a distinct, IFN-γ-negative, neonatal Vγ9Vδ2 T cell population producing IL-17. Furthermore, IL-23 significantly enhanced the expression of a range of cytotoxic mediators (perforin, granzymes, granulysin). Although the costimulatory effect of IL-23 on IFN-γ and cytotoxic mediators was also observed within adult Vγ9Vδ2 T cells, the induction of an IL-17+IFN-γ- subset was unique to neonatal Vγ9Vδ2 T cells. In conclusion, neonatal DC-derived IL-23 combined with specific TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells equipped with a range of cytotoxic mediators and distinct subpopulations producing IFN-γ and IL-17.

Impaired ovarian stimulation during in vitro fertilization in women who are seropositive for hepatitis C virus and seronegative for human immunodeficiency virus.

OBJECTIVE: To analyze the impact of seropositivity with hepatitis C virus (HCV) on in vitro fertilization (IVF) outcomes. DESIGN: Retrospective, case-controlled study. SETTING: Fertility clinic of academic hospital. PATIENT(S): 42 IVF/intracytoplasmic sperm injection cycles in HCV-seropositive women and 84 matched control cycles. INTERVENTION(S): IVF/intracytoplasmic sperm injection treatment for infertility. MAIN OUTCOME MEASURE(S): Ovarian response to stimulation, laboratory findings, and implantation and pregnancy rates. RESULT(S): Absence of ovarian response was statistically significantly higher for HCV-seropositive women compared with controls (10/42 vs 5/84 cycles, respectively). For cycles with oocyte retrieval, HCV-seropositive women required more gonadotropin units compared with controls. The maximum estradiol levels and number of collected oocytes were similar, but HCV-seropositive women had statistically significantly fewer embryos available compared with controls. Embryo morphologic features, number of transferred embryos, and rates of implantation and pregnancy were similar for HCV-seropositive women and controls. CONCLUSION(S): When compared with matched uninfected controls, HCV-seropositive women display a decreased ovarian response.

XSip1 neuralizing activity involves the co-repressor CtBP and occurs through BMP dependent and independent mechanisms.

The DNA-binding transcription factor Smad-interacting protein-1 (Sip1) (also named Zfhx1b/ZEB2) plays essential roles in vertebrate embryogenesis. In Xenopus, XSip1 is essential at the gastrula stage for neural tissue formation, but the precise molecular mechanisms that underlie this process have not been fully identified yet. Here we show that XSip1 functions as a transcriptional repressor during neural induction. We observed that constitutive activation of BMP signaling prevents neural induction by XSip1 but not the inhibition of several epidermal genes. We provide evidence that XSip1 binds directly to the BMP4 proximal promoter and modulates its activity. Finally, by deletion and mutational analysis, we show that XSip1 possesses multiple repression domains and that CtBPs contribute to its repression activity. Consistent with this, interference with XCtBP function reduced XSip1 neuralizing activity. These results suggest that Sip1 acts in neural tissue formation through direct repression of BMP4 but that BMP-independent mechanisms are involved as well. Our data also provide the first demonstration of the importance of CtBP binding in Sip1 transcriptional activity in vivo.