Interleukin 21 inhibits cancer-mediated FOXP3 induction in naïve human CD4 T cells

IL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression. It has also been shown to limit Treg frequencies during tumour-antigen stimulations. However, whether this represents inhibition of FOXP3 induction in naïve CD4 T cells or curtailed expansion of natural Treg remains unclear. Moreover, whether this effect is maintained in an environment of tumour-derived immunosuppressive factors is not known. Here, we show that in the context of a number of cancers, naïve CD45RA+ CD4 T cells are induced to express high levels of FOXP3, and that FOXP3 expression correlates with inhibition of T cell proliferation. FOXP3 expression was most potently induced by tumours secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation. We conclude that Treg induction in naïve T cells is a common phenomenon amongst a number of different cancers and that the ability of IL-21 to counteract this effect is further evidence of its promise in cancer therapy

Subtle oculomotor difficulties and their relation to motor skill in children with autism spectrum disorder

Objectives Sensorimotor difficulties are often reported in autism spectrum disorders (ASD). Visual and motor skills are linked in that the processing of visual information can help in guiding motor movements. The present study investigated oculomotor skill and its relation to general motor skill in ASD by providing a comprehensive assessment of oculomotor control. Methods Fifty children (25 ASD; 25 typically developing [TD]), aged 7–10 years, completed a motor assessment (comprising fine and gross motor tasks) and oculomotor battery (comprising fixation, smooth pursuit, prosaccade and antisaccade tasks). Results No group differences were found for antisaccade errors, nor saccade latencies in prosaccade and antisaccade tasks, but increased saccade amplitude variability was observed in children with ASD, suggesting a reduced consistency in saccade accuracy. Children with ASD also demonstrated poorer fixation stability than their peers and spent less time in pursuit of a moving target. Motor skill was not correlated with saccade amplitude variability. However, regression analyses revealed that motor skill (and not diagnosis) accounted for variance in fixation performance and fast smooth pursuit. Conclusions The findings highlight the importance of considering oculomotor paradigms to inform the functional impact of neuropathologies in ASD and also assessing the presentation of co-occurring difficulties to further our understanding of ASD. Avenues for future research are suggested

Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status

INTRODUCTION: Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk. METHODS: We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status. RESULTS: We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors. CONCLUSIONS: Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors

Btk regulates macrophage polarization in response to lipopolysaccharide

Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (−\−)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(−/−) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(−/−) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(−/−) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (−/−) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation

Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage, similarly to clonal deletion, is driven by intrathymic encounter of agonist self-antigens. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and those that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and -extrinsic determinants may specify the choice between these two fundamentally different T cell fates

Physician-patient communication in rheumatology: a systematic review

The nature of physician–patient interaction can have a significant impact on patient outcomes through information-sharing and disease-specific education that can enhance patients’ active involvement in their care. The aim of this systematic review was to examine all the empirical evidence pertaining to aspects of physician–patient communication and its impact on patient outcomes. A systematic search of five electronic databases (MEDLINE, PsycINFO, EMBASE, CINAHL, and Web of Science) was undertaken from earliest record to December 2016. Studies were eligible if they: (1) included adult participants (18 years or over) with a diagnosis of a rheumatic condition; (2) were of quantitative, qualitative or mixed methods design; (4) were surveys, observational and interventional studies; (5) were published in the English language; and (6) reported findings on either various physician–patient communication aspects alone or in combination with physical and psychological outcomes. Searches identified 455 papers. Following full-text retrieval and assessment for eligibility and quality, ten studies were included in the review; six quantitative, one mixed methods, and three qualitative papers. Higher levels of trust in the physician and active patient participation in the medical consultation were linked to lower disease activity, better global health, less organ damage accrual, greater treatment satisfaction with fewer side effects from the medication, more positive beliefs about control over the disease, and about current and future health. Future research could focus on the design and implementation of interventions incorporating communications skills and patient-education training

The transcription factor BCL-6 controls early development of innate-like T cells

Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence of Bcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, including Zbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development

Subsidiary roles as determinants of subsidiary technology sourcing: empirical evidence from China

Emerging economies have become new destinations for knowledge sourcing, forcing Multinational Enterprises (MNEs) to reconfigure their global innovation strategies and structure. While foreign subsidiaries located in emerging economies were conventionally viewed as having market or efficiency seeking roles, they have started to evolve towards knowledge-seeking roles. We argue that the conventional wisdom shall be reassessed considering this recent shift. We empirically investigate 129 manufacturing MNE subsidiaries of Fortune 500 companies in China, in terms of their roles and sources of technology. Our results indicate that market and knowledge seeking subsidiaries located in China tend to have a positive impact on the generation of new knowledge, either through locally established MNE R&D laboratories or through collaborations with local firms and scientific institutions

A review of the human vs. porcine female genital tract and associated immune system in the perspective of using minipigs as a model of human genital Chlamydia infection

International audienceAbstractSexually transmitted diseases constitute major health issues and their prevention and treatment continue to challenge the health care systems worldwide. Animal models are essential for a deeper understanding of the diseases and the development of safe and protective vaccines. Currently a good predictive non-rodent model is needed for the study of genital chlamydia in women. The pig has become an increasingly popular model for human diseases due to its close similarities to humans. The aim of this review is to compare the porcine and human female genital tract and associated immune system in the perspective of genital Chlamydia infection. The comparison of women and sows has shown that despite some gross anatomical differences, the structures and proportion of layers undergoing cyclic alterations are very similar. Reproductive hormonal cycles are closely related, only showing a slight difference in cycle length and source of luteolysing hormone. The epithelium and functional layers of the endometrium show similar cyclic changes. The immune system in pigs is very similar to that of humans, even though pigs have a higher percentage of CD4+/CD8+ double positive T cells. The genital immune system is also very similar in terms of the cyclic fluctuations in the mucosal antibody levels, but differs slightly regarding immune cell infiltration in the genital mucosa - predominantly due to the influx of neutrophils in the porcine endometrium during estrus. The vaginal flora in Göttingen Minipigs is not dominated by lactobacilli as in humans. The vaginal pH is around 7 in Göttingen Minipigs, compared to the more acidic vaginal pH around 3.5–5 in women. This review reveals important similarities between the human and porcine female reproductive tracts and proposes the pig as an advantageous supplementary model of human genital Chlamydia infection