Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo.

IL-4 promotes Th2 differentiation and provides immunity to helminth infections but is also associated with allergy and asthma. This suggests that precise adjustment of IL-4 responsiveness is needed to correctly balance immune responses. The IL-4Ralpha chain is an essential component of the IL-4 receptor and signals via STAT6. In this study, we show that infection with a helminth pathogen elicited broad upregulation of IL-4Ralpha on bystander CD4+ T cells in the draining lymph node, while simultaneously resulting in the loss of IL-4Ralpha expression on activated Th2 cells. IL-4Ralpha upregulation was restricted to the reactive lymph node, occurred within 4 d of infection, and was driven by an IL-4- and STAT6-dependent mechanism. Mice heterozygous for Stat6 exhibited reduced IL-4Ralpha upregulation and a correspondingly attenuated Th2 response. Indeed, the enhanced IL-4Ralpha upregulation in BALB/c mice, compared with that in C57BL6 mice, predicted their stronger Th2 response. The selective downregulation of IL-4Ralpha on highly activated Th cells was triggered by antigenic stimulation, was accompanied by loss of IL-7Ralpha, and rendered the cells unresponsive to IL-4. Together these data reveal a tightly controlled program of changing IL-4 responsiveness that characterizes the initiation, amplification, and restriction of a Th2 response in vivo.

Psychosocial outcome and resilience after paediatric liver transplantation in young adults.

BACKGROUND AND OBJECTIVE: The long-term psychosocial outcome of young adults after paediatric liver transplantation (LT) was investigated with the focus on day-to-day living. We aimed to capture patients' subjective perceptions of well-being and autonomy based on key physical outcome parameters. METHODS: All patients following paediatric LT at Hannover Medical School born before 2002 with a post-transplant follow-up of at least four years were included in this study. This retrospective observational study compared psychosocial parameters obtained from a self-designed 77-item questionnaire with standard clinical outcome variables. RESULTS: Eighty-two patients (male: 57%) aged 13-41 years were included in the survey within a three-month period (response rate: 41%). With an adherence rate of 33%, all but two patients were immunosuppressed. In total, 53 patients had transitioned to adult care largely without problems. Eighty-three percent (n = 68) evaluated their current health status as "(very) good". Sixty-seven patients (82%) did not experience health-related anxiety in daily life. CONCLUSIONS: Our results demonstrate psychological stability and high self-esteem of young patients, as well as good integration into society and a high degree of normality during daily life after LT. Adherence rates are lower than anticipated and do not correlate with patients' understanding of their medical condition.

Cutting edge: T-bet and IL-27R are critical for in vivo IFN-gamma production by CD8 T cells during infection.

CD8+ T cells are a major source of IFN-gamma, a key effector cytokine in immune responses against many viruses and protozoa. Although the transcription factor T-bet is required for IFN-gamma expression in CD4+ T cells, it is reportedly dispensable in CD8+ T cells, where the transcription factor Eomesodermin is thought to be sufficient. The diverse functions of IFN-gamma are mediated through the IFN-gammaR and STAT1. In CD4+ T cells, STAT1 appears to be critical for the activation of T-bet and IFN-gamma, suggesting an IFN-gamma-dependent positive feedback loop. However, STAT1 can also be activated by other cytokines, including IL-27. In the present study we show that, in contrast to in vitro conditions and the prevailing paradigm, T-bet is critical for the in vivo IFN-gamma production by CD8+ T cells upon infection of mice with diverse pathogens. Whereas IFN-gammaR signals are dispensable for the T-bet-dependent IFN-gamma production, direct IL-27Ralpha signals are critical.

The functional heterogeneity of type 1 effector T cells in response to infection is related to the potential for IFN-gamma production.

The expression of IFN-gamma is a hallmark of Th1 cells and CD8(+) effector T cells and is the signature cytokine of type 1 responses. However, it is not known whether T cells are homogeneous in their capacity to produce IFN-gamma, whether this potential varies between tissues, and how it relates to the production of other effector molecules. In the present study we used bicistronic IFN-gamma-enhanced yellow fluorescent protein (IFN-gamma-eYFP) reporter mice (Yeti) and MHC class I tetramers to directly quantify IFN-gamma expression at the single cell level. The eYFP fluorescence of Th1 cells and CD8(+) effector T cells was broadly heterogeneous even before cell division and correlated with both the abundance of IFN-gamma transcripts and the secretion of IFN-gamma upon stimulation. CD4(+) and CD8(+) T cells of influenza-infected mice revealed a similarly heterogeneous IFN-gamma expression, and eYFP(high) cells were only found in the infected lung. Ag-specific T cells were in all examined tissues eYFP(+), but also heterogeneous in their reporter fluorescence, and eYFP(high) cells were also restricted to the infected lung. A similar heterogeneity was observed in Toxoplasma gondii-infected animals, but eYFP(high) cells were restricted to different tissues. Highly eYFP fluorescent cells produced elevated levels of proinflammatory cytokines and chemokines in addition to IFN-gamma, suggesting their coregulated expression as a functional unit in highly differentiated effector T cells.

Hypoxia decreases active Na transport across primary rat alveolar epithelial cell monolayers.

Hypoxia has been reported to inhibit activity and expression of ion transporters of alveolar epithelial cells. This study extended those observations by investigating the mechanisms underlying inhibition of active Na transport across primary cultured adult rat alveolar epithelial cell monolayers grown on polycarbonate filters. Cell monolayers were exposed to normoxia and hypoxia (1.5% and 5% O(2), 5% CO(2)), and resultant changes in bioelectric properties [i.e., short-circuit current (I(sc)) and transepithelial resistance (R(t))] were measured in Ussing chambers. Results showed that I(sc) decreased with duration of exposure to hypoxia, while relatively little change was observed for R(t). In normoxia, amiloride inhibited approximately 70% of I(sc). The amiloride-sensitive portion of I(sc) decreased over time of exposure to hypoxia, whereas the magnitude of the amiloride-insensitive portion of I(sc) was not affected. Na pump capacity measured after permeabilization of the apical plasma membrane with amphotericin B decreased in monolayers exposed to 1.5% O(2) for 24 h, as did the capacity of amiloride-sensitive Na uptake measured after imposing an apical to basolateral Na gradient and permeabilization of the basolateral membrane. These results demonstrate that exposure to hypoxia inhibits alveolar epithelial Na reabsorption by reducing the rates of both apical amiloride-sensitive Na entry and basolateral Na extrusion.