The role of Notch receptors and ligands in regulation of immune responses

Notch signalling has an important role in the immune system in directing cell fate decisions in a range of diverse cell types. We are beginning to obtain a better understanding of the roles that the different Notch ligands and receptors play in both cellular differentiation of precursor cells and the regulation of immune responses by mature lymphocytes in the periphery. This review will examine the key findings that have emerged in relation to function of Notch in differentiation of T cells, B cells and dendritic cells and how modulation of Notch signalling seems to have potential for therapeutic applications in immune based diseases

T cell homeostasis is regulated by a program of mRNA alternative splicing mediated by heterogeneous nuclear ribonuclear protein L-like (hnRNPLL)

It is essential that the immune system maintains stable numbers of a diverse range of lymphocytes since they play important roles in both innate and adaptive immune responses. T lymphocytes are critical for generating cellular immunity and memory following infections (e.g. CD4+ and CD8+ TCR ab + cells), they are also involved in immune regulation (e.g. CD4+ foxp3+ regulatory T cells), as well as immune surveillance at mucosal surfaces and controlling responses to tumors (e.g. TCR gd + cells, NKT cells). Each cell lineage must be contained within a defined cellular compartment and the size of each compartment is physically constrained due to limitations of nutrients and space. Growth factors that belong to the common gamma chain family of cytokines (e.g. IL-7, IL-15 and IL-2) are particularly important for T cell survival but the molecular regulation of lymphocyte survival remains poorly understood. However our understanding of the molecular mechanisms that control T cell homeostasis remains poorly defined. We have recently identified a novel role for the nuclear protein heterogeneous nuclear ribonuclear protein L-like (hnRNPLL) for the homeostasis of CD4+ and CD8+ T cells in the peripheral immune system through the characterization of a mouse strain derived from an ENU mutagenesis screen (1). The thunder mouse strain was identified on the basis of reduced numbers of peripheral T cells and we have gone onto to show that the cellular phenotype is caused by a hypomorphic mutation in the Hrnpll gene which controls mRNA alternative splicing. We have used a genomic approach to study the target genes in naïve and memory T cells whose splicing is dependent on hnRNPLL. This revealed that the transition from the naïve to memory phenotype involves a program of mRNA alternative splicing that involves hundreds of genes. The thunder mutation does not affect T cell development but it has a non redundant role in regulating the persistence of T cells in the peripheral immune system. These studies have uncovered that temporal changes in mRNA alternative splicing underpins the control T cell homeostasis in vivo that occurs in response to growth factor and antigen receptor signalling. (1) 1. Wu, Z et al 2008. Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL. Immunity 29: 863-875

Mechanisms that regulate peripheral immune responses to control organ specific autoimmunity

The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This review will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T cell effector responses and the development of organ specific autoimmune diseases such as type 1 diabetes

Understanding the psychology of seeking support to increase health science student engagement in academic support services. A Practice report

Increasing student engagement within higher education academic support services is a constant challenge. Whilst engagement with support is positively associated with successful retention, and non-engagement connected to attrition, the most vulnerable students are often the least likely to engage. Our data has shown that Health Science students are reluctant to engage with academic support services despite being made aware of their academic deficiencies. The psychology of seeking support was used as a lens to identify some of the multifaceted issues around student engagement. The School of Health Sciences made attendance at support courses compulsory for those students who were below the benchmark score in a post entrance literacy test. Since the policy change was implemented, there has been a 50% reduction in the fail rate of at risk students in a core literacy unit. These findings are encouraging and will help reduce student attrition in the long term

The role of the Nef protein in MHC-I downregulation and viral immune evasion by HIV-1

The Nef protein is a major determinant of pathogenicity caused by the human immunodeficiency virus (HIV) and is encoded by the nef gene within the genomes of primate lentiviruses HIV-1, HIV-2 and simian immunodeficiency virus (SIV). The HIV Nef protein subverts the intracellular membrane traffic to mediate endocytosis of a number of cell surface receptors to accelerate their degradation. In this review we will examine how the multifunctional Nef can mediate down regulation of the Major histocompatibility Complex (MHC) I complex proteins from the surface of infected cells as a means of immune evasion by HIV. By selectively downregulating MHC-I HLA-A and HLA-B haplotypes, while maintaining the expression of HLA-C, HLA-E and HLA-G the HIV virus is able to avoid recognition by both the NK and cytotoxic CD8+ T cell effector responses. This protects the virus from cell lysis and enables it to hide from the cell-mediated immune system

Role of the gut microbiota as a natural adjuvant for vaccine

Vaccines have provided the most beneficial contribution to public health. Generating antigen specific antibody responses and long lasting memory are crucial for the protective immunity offered by vaccination. Unfortunately, not all individuals respond in the same manner to vaccine formulations. The microbiota is established during postnatal development and remains relatively stable for long periods. Our understanding that the microbiota can have beneficial effects on human health has led immunologists to investigate how these organisms may shape the innate and adaptive immune responses of the host. In this review we examine the impact of the microbiota on the host immune responses to vaccines and explore the possibility of how the commensal bacteria may act as natural adjuvants to enhance systemic immune responses to vaccines

The use of genomewide ENU mutagenesis screens to unravel complex mammalian traits: Identifying genes that regulate organ-specific and systemic autoimmunity

T-cell development is perhaps one of the best understood processes of mammalian cell differentiation, as many of the genes and pathways have been identified. By contrast, relatively little is known about the genes and pathways involved in immunological tolerance to self-antigens. Here, we describe the challenges associated with a genomewide screen designed at identifying new immune regulatory genes that uses a model of organ-specific autoimmunity leading to type 1 diabetes. The successful propagation and identification of the new gene variants will shed light on the various developmental checkpoints in lymphocyte development that are crucial for establishing tolerance to self-antigens

The role of alternative splicing in the control of immune homeostasis and cellular differentiation

Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, but when dysregulation in splicing occurs this can have important impact on health and disease. Alternative splicing is widely used in the mammalian immune system to control the development and function of antigen specific lymphocytes. In this review we will examine the splicing of pre-mRNAs yielding key proteins in the immune system that regulate apoptosis, lymphocyte differentiation, activation and homeostasis, and discuss how defects in splicing can contribute to diseases. We will describe how disruption to trans-acting factors, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), can impact on cell survival and differentiation in the immune system

Idiopathic pulmonary fibrosis and a role for autoimmunity

Idiopathic Pulmonary Fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is typically associated with extensive and progressive fibrosis, is fatal and has limited treatment options. Characteristically IPF patients display large lymphocyte aggregates composed of CD3+ T cells and CD20+ B cells within the lung tissue that are located near sites of active fibrosis. In addition, IPF patients can have autoantibodies to a range of host antigens, suggesting a breakdown in immunological tolerance. In this review we examine the role of T and B cells in IPF pathogenesis and discuss how loss of self- tolerance to lung specific proteins could exacerbate disease progression in IPF. We discuss what these results mean in terms of future prospects for immunotherapy of IPF

Mesothelial cells regulate immune responses in health and disease: Role for immunotherapy in malignant mesothelioma

Highlights: Mesothelial and immune cell interactions play a crucial role in tissue homeostasis in the serosal cavities such as the pleura. Mesothelin is viewed as an attractive target for solid tumors, including malignant mesothelioma. Checkpoint inhibitor therapy has shown variable efficacy against malignant mesothelioma. CAR T cell therapies are being evaluated for malignant mesothelioma. Treatment of malignant mesothelioma will require multimodality approaches with immunotherapy central to future therapeutic approaches. The mesothelium when first described was thought to function purely as a non-adhesive surface to facilitate intracoelomic movement of organs. However, the mesothelium is now recognized as a dynamic cellular membrane with many important functions that maintain serosal integrity and homeostasis. For example, mesothelial cells interact with and help regulate the body’s inflammatory and immune system following infection, injury, or malignancy. With recent advances in our understanding of checkpoint molecules and the advent of novel immunotherapy approaches, there has been an increase in the number of studies examining mesothelial and immune cell interaction, in particular the role of these interactions in malignant mesothelioma. This review will highlight some of the recent advances in our understanding of how mesothelial cells help regulate serosal immunity and how in a malignant environment, the immune system is hijacked to stimulate tumor growth. Ways to treat mesothelioma using immunotherapy approaches will also be discussed