Biallelic mutations in IRF8 impair human NK cell maturation and function

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8–/–, but not Irf8+/–, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense

Long-Term Persistence of Functional Thymic Epithelial Progenitor Cells In Vivo under Conditions of Low FOXN1 Expression

Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/- mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro

A Simple Model System Enabling Human CD34+ Cells to Undertake Differentiation Towards T Cells

Channelling the development of haematopoietic progenitor cells into T lymphocytes is dependent upon a series of extrinsic prompts whose temporal and spatial sequence is critical for a productive outcome. Simple models of human progenitor cells development depend in the main on the use of xenogeneic systems which may provide some limitations to development. Here we provide evidence that a simple model system which utilises both human keratinocyte and fibroblast cell lines arrayed on a synthetic tantalum coated matrix provides a permissive environment for the development of human CD34⁺ haematopoietic cells into mature CD4⁺ or CD8⁺ T lymphocytes in the presence of Interleukin 7 (IL-7), Interleukin 15 (IL-15) and the Fms-like tyrosine kinase 3 ligand (Flt-3L). This system was used to compare the ability of CD34(+) cells to produce mature thymocytes and showed that whilst these cells derived from cord blood were able to productively differentiate into thymocytes the system was not permissive for the development of CD34(+) cells from adult peripheral blood. Our study provides direct evidence for the capacity of human cord blood CD34(+) cells to differentiate along the T lineage in a simple human model system. Productive commitment of the CD34⁺ cells to generate T cells was found to be dependent on a three-dimensional matrix which induced the up-regulation of the Notch delta-like ligand 4 (Dll-4) by epithelial cells

Exploring non-participation in primary care physical activity interventions: PACE-UP trial interview findings

Background: Trials in primary care to increase physical activity (PA) typically experience poor recruitment rates and may not recruit those with lower PA levels and who are most in need of the intervention. Despite the well-publicised benefits of physical activity, the majority of adults in the UK remain inactive and therefore at greater risk of many health problems. Our aim was to investigate the reasons for non-participation in the PACE-UP trial, which is a primary care pedometer based walking intervention. This is important for successful recruitment and retention in future PA trials and programmes. Method: We conducted semi-structured audio-recorded telephone interviews with thirty 45-75 year olds purposively sampled from those declining participation in the PACE-UP trial. Recruitment continued until data saturation and a demographically balanced sample was achieved. Interviews were transcribed verbatim, coded and subjected to thematic analysis. Results: Interviewees supported walking as suitable exercise for most people in this age group, recognised the importance of this type of research and general practice as an appropriate setting. Key reasons for declining were: the perception of being already ‘too active’; existing medical conditions; work; travel and other commitments. Less frequently cited reasons included reluctance to be randomised, the intervention’s duration, wearing a pedometer, perceived inappropriateness of trial literature and a preference for a different kind of PA or for a group activity. Conclusions: Whilst most interviewees perceived themselves to be sufficiently active, an important minority did not participate due to existing medical conditions and other commitments. Recruitment to future PA trials might be improved by tailoring activity to compensate for medical problems, and adapting PA interventions to fit around work and travel commitments. Ensuring patient literature is succinct and inclusive and equipment is user-friendly is important. Primary care is seen as an appropriate setting for PA trials and programmes.The PACE-UP trial was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number HTA 10/32/02 ISRCTN42122561)

(Latent) Potentials to Incorporate and Improve Environmental Knowledge Using African Languages in Agriculture Lessons in Malawi:

In their official language policy, nearly all Sub-Saharan African states use their indigenous language(s) as Language of Learning and Teaching (LoLT) only at the beginning of primary schools. This is also the case in Malawi. The curricula in the various school subjects are also highly dominated by ‘Western’ ideas and include very little Indigenous Knowledge (IK). Nevertheless, indigenous languages are frequently used during lessons. This research focused on answering the following questions: How is a meaningful Science Education for pupils in Malawi possible? Does the inclusion of IK and teaching through African Languages assist pupils in any way? Research was done in the Northern Region of Malawi. To obtain a better understanding, semi-structured interviews and ethnographic observations were conducted. The main focus of these interviews was on the subject of ‘Agriculture’

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses