Robert J Salmond

University of Leeds · Leeds Institute of Medical Research at St. James's

T cells must be tolerant of self antigens to avoid autoimmunity but responsive to foreign antigens to provide protection against infection. We found that in both naive T cells and effector T cells, the tyrosine phosphatase PTPN22 limited signaling via the T cell antigen receptor (TCR) by weak agonists and self antigens while not impeding responses...

Adoptive T cell therapy (ACT) has been established as an efficacious methodology for the treatment of cancer. Identifying targets to enhance the antigen recognition, functional capacity and longevity of T cells has the potential to broaden the applicability of these approaches in the clinic. We previously reported that targeting expression of phosp...

T cell receptor (TCR) triggering by antigen results in metabolic reprogramming that, in turn, facilitates T cells' exit from quiescence. The increased nutrient requirements of activated lymphocytes are met in part by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids and glucose from the environment. However,...

Transforming growth factor β (TGFβ) is important in maintaining self-tolerance and inhibits T cell reactivity. We show that CD8⁺ T cells that lack the tyrosine phosphatase Ptpn22, a major predisposing gene for autoimmune disease, are resistant to the suppressive effects of TGFβ. Resistance to TGFβ suppression, while disadvantageous in autoimmunity,...

The successful implementation of immunotherapies has provided new impetus in the fight against cancer. Antibody‐mediated blockade of immune checkpoint molecules PD‐1 / PD‐L1 and CTLA‐4 has had a dramatic impact upon the treatment of previously intractable cancers such as malignant melanoma, whilst adoptive cell therapies using chimeric antigen rece...

Background Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phospho...

Simple Summary T cells are a subset of white blood cells that play essential roles in immune protection from a wide range of infectious diseases as well as cancer. By contrast, when immune responses are not controlled properly, T cells can promote damaging inflammation such as that seen in autoimmune diseases. Therefore, the activation of immune re...

T cell activation is dependent upon the integration of antigenic, co-stimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and e...

T cell activation is dependent upon the integration of antigenic, costimulatory and cytokine-derived signals and the availability and acquisition of nutrients from the environment. Furthermore, T cell activation is accompanied by reprogramming of cellular metabolism to provide the energy and building blocks for proliferation, differentiation and ef...

In a new study, researchers identified protein tyrosine phosphatase PTP1B as an inhibitor of cytokine receptor signalling and demonstrated that blocking activity or expression of this enzyme unleashes T cell responses to cancer.

T cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain...

BACKGROUND Up to 60% of melanoma patients develop brain metastases (BrM). These patients have a poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICI) targeting Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and Programmed cell death protein-1 (PD-1) have revolutionized the treatment of melanoma and their efficacy ha...

BACKGROUND Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-...

Patients with glioblastoma (GBM) have a poor prognosis, and inefficient delivery of drugs to tumors represents a major therapeutic hurdle. Hematopoietic stem cell (HSC)-derived myeloid cells efficiently home to GBM and constitute up to 50% of intratumoral cells, making them highly appropriate therapeutic delivery vehicles. Because myeloid cells are...

T cell receptor triggering by antigen results in metabolic reprogramming that, in turn, facilitates T cells exit from quiescence. The increased nutrient requirements of activated lymphocytes are met in part by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids and glucose from the environment. However, the rol...

T cell activation, differentiation and effector function is intrinsically linked to the regulation of metabolic pathways. Evidence has shown that inflammatory T cell responses are dependent upon the adoption of aerobic glycolytic metabolism. Furthermore, activation and regulation of the mechanistic target of rapamycin signaling pathway serves a key...

A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22, that encodes a tyrosine phosphatase, has been associated with the development of several autoimmune diseases including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates t...

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metas...

The cytoplasmic phosphatase, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), is a negative regulator of T cell signaling. Genome-wide association studies have shown that single-nucleotide polymorphisms in PTPN22 confer an increased risk of developing multiple autoimmune diseases in humans. The precise function of PTPN22 and how the varia...

Ag-dependent activation of naive T cells induces dramatic changes in cellular metabolism that are essential for cell growth, division, and differentiation. In recent years, the serine/threonine kinase mechanistic target of rapamycin (mTOR) has emerged as a key integrator of signaling pathways that regulate these metabolic processes. However, the ro...

The non-receptor tyrosine phosphatase PTPN22 has a vital function in inhibiting antigen-receptor signaling in T cells, whilst polymorphisms in the PTPN22 gene are important risk alleles in human autoimmune diseases. We recently reported that a key physiological function of PTPN22 was to prevent naïve T cell activation and effector cell responses in...

In recent years, several distinct innate lymphoid cell populations (ILC) have been characterized in mice and humans. Group 2 ILC function as a rapid responder population in type 2 immune responses. Thus, a wealth of data has implicated an important role for ILC2 in immunity to parasitic infection and in immune pathology in inflammatory and allergic...

Th9 cells protect hosts against helminthic infection but also mediate allergic disease. Here we show that nitric oxide (NO) promotes Th9 cell polarization of murine and human CD4(+) T cells. NO de-represses the tumour suppressor gene p53 via nitrosylation of Mdm2. NO also increases p53-mediated IL-2 production, STAT5 phosphorylation and IRF4 expres...

CD4(+) T cells have long been grouped into distinct helper subsets on the basis of their cytokine-secretion profile. In recent years, several subsets of innate lymphoid cell have been described as key producers of these same Th-associated cytokines. However, the functional relationship between Th cells and innate lymphoid cells (ILCs) remains uncle...

Introduction Type-2 innate lymphoid cells (ILC2) are a novel subset of immune cells characterised by their responsiveness to interleukin (IL)-33 and their production of type-2 cytokines (including IL-5, IL-9, IL-13). ILC2 have a variety of roles in lung inflammation and repair. Their interaction with innate immune cells has been shown, however thei...

Background: The IL-1 family cytokine IL-33 is involved in the induction of airway inflammation in allergic patients and after viral infection. Several cell types, including CD4(+) T(H)2 cells and the recently described type 2 innate lymphoid cells (ILCs), are targets for IL-33, yet the mechanisms by which this cytokine modulates their activation a...

Interleukin (IL)-33 is a member of the IL-1 cytokine family that has been shown to play an important role in the induction and effector phases of type 2 immune responses. Both innate and adaptive immunity are regulated by IL-33, and many studies have shown disease-associated functions for this cytokine. Recently, IL-33 has been implicated in the fu...

Introduction IL-33 is an innate cytokine that promotes Th2 responses in both the innate and the adaptive immune systems, with an established role in allergic airway inflammation.1 The signalling pathway of IL-33/ ST2 is incompletely understood and the cells driving IL-33-mediated inflammation have remained elusive. Nuocytes, also known as natural h...

The mammalian target of rapamycin (mTOR) integrates signalling responses to growth factors and nutrients. The macrolide rapamycin inhibits mTOR function and has been used extensively to demonstrate a critical role for mTOR in immune responses. This mini-review summarizes recent evidence demonstrating an integral role for mTOR in the differentiation...

T-cell development is critically dependent on the activities of the Src-family kinases p56(lck) and p59(fyn). While Lck plays a dominant role in the initiation of T-cell receptor (TCR) signaling and in thymocyte differentiation, Fyn plays a more subtle regulatory role. We sought to determine the role of intracellular localization in the differing f...

Naive T lymphocytes maintain a quiescent resting state until they encounter antigen whereupon they undergo a switch in their metabolic program in preparation for proliferation and differentiation. This activation process involves a dramatic upregulation of protein synthesis that is essential for cell growth and the differentiation of effector funct...

Ribosomal protein S6 (rpS6) is a key component of the translational machinery in eukaryotic cells and is essential for ribosome biogenesis. rpS6 is phosphorylated on evolutionarily conserved serine residues, and data indicate that rpS6 phosphorylation might regulate cell growth and protein synthesis. Studies in cell lines have shown an important ro...

T-cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T-cell repertoire, while activation of naive peripheral T cells induces prolif...

The CD45 tyrosine phosphatase is required for T cell development and function by virtue of its role as a positive regulator of src family kinase activity. In addition, recent data have highlighted that CD45 also acts as a negative regulator of Lck function by dephosphorylation of critical tyrosine residues. Lck functionality and TCR responsiveness...

In naive T cells, engagement of the TCR with agonist peptide:MHC molecules leads to phosphorylation of key intracellular signaling intermediates within seconds and this peaks within minutes. However, the cell does not commit to proliferation and IL-2 cytokine production unless receptor contact is sustained for several hours. The biochemical basis f...

The molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45R...

The src homology 2 (SH2) domain containing tyrosine phosphatase SHP2 (also referred to as SHP-2) is ubiquitously expressed in mammalian tissues and has been shown to be essential for embryonic development, haematopoiesis and signalling downstream of a variety of growth factors. Dysregulation of SHP2 function or expression has recently been implicat...

The src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) plays an important role in development and in growth factor receptor signaling pathways, yet little is known of its role in the immune system. We generated mice expressing a dominant-negative version of the protein, SHP2(CS), specifically in T cells. In SHP2(CS) mice, T cell develop...

The nontoxic B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule that acts both as an adjuvant and to stimulate immune deviation processes, resulting in the suppression of Th1-associated inflammatory responses. The ability of EtxB to alter immune reactivity is dependent on its ability to modulate immun...

Receptor-binding by the B-subunit of Escherichia coli heat-labile enterotoxin (EtxB) induces apoptosis of peripheral CD8(+), but not CD4(+) T-cells. Given that peripheral CD8(+) and CD4(+) T cells arise from a common developmental pathway in the thymus, we investigated the effects of EtxB on different thymocyte populations. We show that the acquisi...

The homopentameric B-subunit components of Escherichia coli heat-labile enterotoxin (EtxB) and cholera toxin (CtxB) possess the capacity to enter mammalian cells and to activate cell-signaling events in leukocytes that modulate immune cell function. Both properties have been attributed to the ability of the B subunits to bind to GM1-ganglioside rec...

The role of cholera toxin and heat-labile enterotoxin in the pathogenesis of diarrhoeal disease has been well documented for many years. In addition to these deleterious effects, a wealth of data is accumulating that suggests that these toxins and their subunits might be used to modulate immune responses in a variety of beneficial ways. In this reg...

The B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule capable of treating and preventing autoimmune disease. These properties result from its ability to bind to glycolipid receptors, principally G(M1) ganglioside, and modulate immune cell function. EtxB receptor binding causes B cell activation, modu...

Thesis (Ph. D.)--University of Bristol, 2001.