Life Sciences Research for Lifelong Health

Publications

The Babraham Institute Publications database contains details of all publications resulting from our research groups and scientific services.

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Title / Authors / Details Open Access Download

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion.
Johnston JM, Angyal A, Bauer RC, Hamby S, Suvarna SK, Baidžajevas K, Hegedus Z, Dear TN, Turner M, , Wilson HL, Goodall AH, Rader DJ, Shoulders CC, Francis SE, Kiss-Toth E

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced expression mediates the strong genetic association between the locus and increased CHD risk in man. However, we report here that myeloid-specific (m) deficiency reduces early atheroma formation and that m transgene expression increases atherogenesis. Mechanistically, m increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As and RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

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Science advances, 5, 2375-2548, eaax9183, 2019

PMID: 31692955

Open Access

Diverse Human V antibody fragments with bio-therapeutic properties from the Crescendo Mouse.
Teng Y, Young JL, Edwards B, Hayes P, Thompson L, Johnston C, Edwards C, Sanders Y, Writer M, Pinto D, Zhang Y, Roode M, Chovanec P, Matheson L, Corcoran AE, Fernandez A, Montoliu L, Rossi B, Tosato V, Gjuracic K, Nikitin D, Bruschi C, McGuinness B, Sandal T, Romanos M

We describe the 'Crescendo Mouse', a human V transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3' regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely 'heavy chain only' antibodies. Heavy chain variable (V) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human V that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human V fragments, or Humabody® V, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® V specific for human IL17A and IL17RA.

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New biotechnology, , 1876-4347, , 2019

PMID: 31600579

Longitudinal In Vivo Assessment of Host-Microbe Interactions in a Murine Model of Pulmonary Aspergillosis.
Saini S, Poelmans J, Korf H, Dooley JL, Liang S, Manshian BB, Verbeke R, Soenen SJ, Vande Velde G, Lentacker I, Lagrou K, Liston A, Gysemans C, De Smedt SC, Himmelreich U

The fungus Aspergillus fumigatus is ubiquitous in nature and the most common cause of invasive pulmonary aspergillosis (IPA) in patients with a compromised immune system. The development of IPA in patients under immunosuppressive treatment or in patients with primary immunodeficiency demonstrates the importance of the host immune response in controlling aspergillosis. However, study of the host-microbe interaction has been hampered by the lack of tools for their non-invasive assessment. We developed a methodology to study the response of the host's immune system against IPA longitudinally in vivo by using fluorine-19 magnetic resonance imaging (F MRI). We showed the advantage of a perfluorocarbon-based contrast agent for the in vivo labeling of macrophages and dendritic cells, permitting quantification of pulmonary inflammation in different murine IPA models. Our findings reveal the potential of F MRI for the assessment of rapid kinetics of innate immune response against IPA and the permissive niche generated through immunosuppression.

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iScience, 20, 2589-0042, 184-194, 2019

PMID: 31581067

Open Access

IL-7R is essential for leukemia-initiating cell activity and pathogenesis of T-cell acute lymphoblastic leukemia.
González-García S, Mosquera M, Fuentes P, Palumbo T, Escudero A, Pérez-Martínez A, Ramírez M, Corcoran AE, Toribio ML

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from the dysregulation of signaling pathways that control intrathymic T-cell development. Relapse rates are still significant and prognosis is particularly bleak for relapsed patients. Therefore, development of novel therapies specifically targeting pathways controlling leukemia-initiating cell (LIC) activity is mandatory for fighting refractory T-ALL. The interleukin-7 receptor (IL-7R) is a crucial T-cell developmental pathway commonly expressed in T-ALL, which has been implicated in leukemia progression. However, the significance of IL-7R/IL-7 signaling in T-ALL pathogenesis and its contribution to disease relapse remain unknown. To directly explore whether IL-7R targeting may be therapeutically efficient against T-ALL relapse, we focused here on a known Notch1-induced T-ALL model, since a majority of T-ALL patients harbor activating mutations in , which is a transcriptional regulator of IL-7R expression. Using loss-of-function approaches, we show that -deficient, but not wild type, mouse hematopoietic progenitors transduced with constitutively active Notch1 failed to generate leukemia upon transplantation into immunodeficient mice, thus providing formal evidence that IL-7R function is essential for Notch1-induced T-cell leukemogenesis. Moreover, we demonstrate that IL-7R expression is an early functional biomarker of T-ALL cells with LIC potential, and demonstrate that impaired IL-7R signaling hampers engraftment and progression of patient-derived T-ALL xenografts. Notably, we show that IL-7R-dependent LIC activity and leukemia progression can be extended to human B-ALL. These results have important therapeutic implications, highlighting the relevance that targeting normal IL-7R signaling may have in future therapeutic interventions, particularly for preventing T-ALL (and B-ALL) relapse.

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Blood, , 1528-0020, , 2019

PMID: 31530562

Genome-Wide Measurement and Computational Analysis of Transcription Factor Binding and Chromatin Accessibility in Lymphocytes.
Sadiyah MF, Roychoudhuri R

Cells of the adaptive immune system, including CD4 and CD8 T cells, as well as B cells, possess the ability to undergo dynamic changes in population size, differentiation state, and function to counteract diverse and temporally stochastic threats from the external environment. To achieve this, lymphocytes must be able to rapidly control their gene-expression programs in a cell-type-specific manner and in response to extrinsic signals. Such capacity is provided by transcription factors (TFs), which bind to the available repertoire of regulatory DNA elements in distinct lymphocyte subsets to program cell-type-specific gene expression. Here we provide a set of protocols that utilize massively parallel sequencing-based approaches to map genome-wide TF-binding sites and accessible chromatin, with consideration of the unique aspects and technical issues facing their application to lymphocytes. We show how to computationally validate and analyze aligned data to map differentially enriched/accessible sites, identify enriched DNA sequence motifs, and detect the position of nucleosomes adjacent to accessible DNA elements. These techniques, when applied to immune cells, can enhance our understanding of how gene-expression programs are controlled within lymphocytes to coordinate immune function in homeostasis and disease. © 2019 by John Wiley & Sons, Inc.

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Current protocols in immunology, 126, 1934-368X, e84, 2019

PMID: 31483104

Embryonic FAP lymphoid tissue organizer cells generate the reticular network of adult lymph nodes.
Denton AE, Carr EJ, Magiera LP, Watts AJB, Fearon DT

The induction of adaptive immunity is dependent on the structural organization of LNs, which is in turn governed by the stromal cells that underpin LN architecture. Using a novel fate-mapping mouse model, we trace the developmental origin of mesenchymal LN stromal cells (mLNSCs) to a previously undescribed embryonic fibroblast activation protein-α (FAP) progenitor. FAP cells of the LN anlagen express lymphotoxin β receptor (LTβR) and vascular cell adhesion molecule (VCAM), but not intercellular adhesion molecule (ICAM), suggesting they are early mesenchymal lymphoid tissue organizer (mLTo) cells. Clonal labeling shows that FAP progenitors locally differentiate into mLNSCs. This process is also coopted in nonlymphoid tissues in response to infection to facilitate the development of tertiary lymphoid structures, thereby mimicking the process of LN ontogeny in response to infection.

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The Journal of experimental medicine, 216, 1540-9538, 2242-2252, 2019

PMID: 31324739

Open Access

The murine IgH locus contains a distinct DNA sequence motif for the chromatin regulatory factor CTCF.
Ciccone DN, Namiki Y, Chen C, Morshead KB, Wood AL, Johnston CM, Morris JW, Wang Y, Sadreyev R, Corcoran AE, Matthews AGW, Oettinger MA

Antigen receptor assembly in lymphocytes involves stringently regulated coordination of specific DNA rearrangement events across several large chromosomal domains. Previous studies indicate that transcription factors such as paired box 5 (PAX5), Yin Yang 1 (YY1), and CCCTC-binding factor (CTCF) play a role in regulating the accessibility of the antigen receptor loci to the V(D)J recombinase, which is required for these rearrangements. To gain clues about the role of CTCF binding at the murine immunoglobulin heavy chain (IgH) locus, we utilized a computational approach that identified 144 putative CTCF-binding sites within this locus. We found that these CTCF sites share a consensus motif distinct from other CTCF sites in the mouse genome. Additionally, we could divide these CTCF sites into three categories: intergenic sites remote from any coding element, upstream sites present within 8 kb of the VH-leader exon, and recombination signal sequence (RSS)-associated sites characteristically located at a fixed distance (~18 bp) downstream of the RSS. We noted that the intergenic and upstream sites are located in the distal portion of the VH locus, whereas the RSS-associated sites are located in the DH-proximal region. Computational analysis indicated that the prevalence of CTCF-binding sites at the IgH locus is evolutionarily conserved. In all species analyzed, these sites exhibit a striking strand-orientation bias, with > 98% of the murine sites being present in one orientation with respect to VH gene transcription. Electrophoretic mobility shift and enhancer-blocking assays and ChIP-chip analysis confirmed CTCF binding to these sites both in vitro and in vivo.

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The Journal of biological chemistry, , 1083-351X, , 2019

PMID: 31285261

Open Access

Regulatory T cells in cancer: where are we now?
Gallimore A, Quezada SA, Roychoudhuri R

There have been substantial strides forward in our understanding of the contribution of regulatory T (Treg) cells to cancer immunosuppression. In this issue, we present a series of papers highlighting emerging themes on this topic relevant not only to our understanding of the fundamental biology of tumour immunosuppression but also to the design of new immunotherapeutic approaches. The substantially shared biology of CD4 conventional T (Tconv) and Treg cells necessitates a detailed understanding of the potentially opposing functional consequences that immunotherapies will have on Treg and Tconv cells, a prominent example being the potential for Treg-mediated hyperprogressive disease following anti-PD-1 therapy. Such understanding will aid patient stratification and the rational design of combination therapies. It is also becoming clear, however, that Treg cells within tumours exhibit distinct biological features to both Tconv cells and Treg cells in other tissues. These distinct features provide the opportunity for development of targeted immunotherapies with greater efficacy and reduced potential for inducing systemic toxicity.

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Immunology, 157, 1365-2567, 187-189, 2019

PMID: 31225653

The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes.
Hill DL, Pierson W, Bolland DJ, Mkindi C, Carr EJ, Wang J, Houard S, Wingett SW, Audran R, Wallin EF, Jongo SA, Kamaka K, Zand M, Spertini F, Daubenberger C, Corcoran AE, Linterman MA

The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE-formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRβ clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines.

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The Journal of experimental medicine, , 1540-9538, , 2019

PMID: 31175140

Open Access

Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2.
Trulley P, Snieckute G, Bekker-Jensen D, Menon MB, Freund R, Kotlyarov A, Olsen JV, Diaz-Muñoz MD, Turner M, Bekker-Jensen S, Gaestel M, Tiedje C

Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5' UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties.

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Cell reports, 27, 2211-1247, 2859-2870.e6, 2019

PMID: 31167133

Open Access

Heterochronic faecal transplantation boosts gut germinal centres in aged mice.
Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, Linterman MA

Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system; however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer's patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli.

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Nature communications, 10, 2041-1723, 2443, 2019

PMID: 31164642

Open Access

Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition.
Habets RA, de Bock CE, Serneels L, Lodewijckx I, Verbeke D, Nittner D, Narlawar R, Demeyer S, Dooley J, Liston A, Taghon T, Cools J, de Strooper B

Given the high frequency of activating mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role.

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Science translational medicine, 11, 1946-6242, , 2019

PMID: 31142678

MicroRNA-155 is essential for the optimal proliferation and survival of plasmablast B cells.
Arbore G, Henley T, Biggins L, Andrews S, Vigorito E, Turner M, Leyland R

A fast antibody response can be critical to contain rapidly dividing pathogens. This can be achieved by the expansion of antigen-specific B cells in response to T-cell help followed by differentiation into plasmablasts. MicroRNA-155 (miR-155) is required for optimal T-cell-dependent extrafollicular responses via regulation of PU.1, although the cellular processes underlying this defect are largely unknown. Here, we show that miR-155 regulates the early expansion of B-blasts and later on the survival and proliferation of plasmablasts in a B-cell-intrinsic manner, by tracking antigen-specific B cells in vivo since the onset of antigen stimulation. In agreement, comparative analysis of the transcriptome of miR-155-sufficient and miR-155-deficient plasmablasts at the peak of the response showed that the main processes regulated by miR-155 were DNA metabolic process, DNA replication, and cell cycle. Thus, miR-155 controls the extent of the extrafollicular response by regulating the survival and proliferation of B-blasts, plasmablasts and, consequently, antibody production.

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Life science alliance, 2, 2575-1077, , 2019

PMID: 31097471

Open Access

Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ.
Swan DJ, Aschenbrenner D, Lamb CA, Chakraborty K, Clark J, Pandey S, Engelhardt KR, Chen R, Cavounidis A, Ding Y, Krasnogor N, Carey CD, Acres M, Needham S, Cant AJ, Arkwright PD, Chandra A, Okkenhaug K, Uhlig HH, Hambleton S

Haematologica, , 1592-8721, , 2019

PMID: 31073077

Open Access

FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.
Espéli M, Bashford-Rogers R, Sowerby JM, Alouche N, Wong L, Denton AE, Linterman MA, Smith KGC

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.

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Nature communications, 10, 2041-1723, 1970, 2019

PMID: 31036800

Regulation of regulatory T cells in cancer.
Stockis J, Roychoudhuri R, Halim TYF

The inflammatory response to transformed cells forms the cornerstone of natural or therapeutically-induced protective immunity to cancer. Regulatory T (Treg) cells are known for their critical role in suppressing inflammation, and therefore can antagonize effective anti-cancer immune responses. As such, Treg cells can play detrimental roles in tumour progression and in the response to both conventional and immune-based cancer therapy. Recent advances in our understanding of Treg cells reveal complex niche-specific regulatory programs and functions, which are likely to extrapolate to cancer. The regulation of Treg cells is reliant on upstream cues from haematopoietic and non-immune cells, which dictates their genetic, epigenetic, and downstream functional programmes. In this Review we will discuss how Treg cells are themselves regulated in normal and transformed tissues, and the implications of this crosstalk on tumour growth. This article is protected by copyright. All rights reserved.

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Immunology, , 1365-2567, , 2019

PMID: 31032905

Open Access

RNA binding proteins in hematopoiesis and hematological malignancy.
Hodson DJ, Screen M, Turner M

RNA binding proteins (RBPs) regulate fundamental processes such as differentiation and self-renewal by enabling the dynamic control of protein abundance or isoforms, or through the regulation of non-coding RNA. RBPs are increasingly appreciated as being essential for normal hematopoiesis and they are understood to play fundamental roles in hematological malignancies by acting as oncogenes or tumor suppressors. Alternative splicing has been shown to play roles in the development of specific hematopoietic lineages and sequence specific mutations in RBPs lead to dysregulated splicing in myeloid and lymphoid leukemias. RBPs that regulate translation contribute to the development and function of hematological lineages, act as nodes for the action of multiple signaling pathways and contribute to hematological malignancies. These insights broaden our mechanistic understanding of the molecular regulation of hematopoiesis and offer opportunities to develop disease biomarkers and new therapeutic modalities.

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Blood, , 1528-0020, , 2019

PMID: 30967369

Open Access

Inborn errors of immunity: single mutations unravel mechanisms of immune disease.
Liston A, Humblet-Baron S

Immunology and cell biology, , 1440-1711, , 2019

PMID: 30942931

Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression.
Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, Ulas T, Papantonopoulou O, Van Eck M, Auphan-Anezin N, Bebien M, Verthuy C, Vu Manh TP, Turner M, Dalod M, Schultze JL, Lawrence T

Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy.

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Cell metabolism, , 1932-7420, , 2019

PMID: 30930171

T cell stemness and dysfunction in tumors are triggered by a common mechanism.
Vodnala SK, Eil R, Kishton RJ, Sukumar M, Yamamoto TN, Ha NH, Lee PH, Shin M, Patel SJ, Yu Z, Palmer DC, Kruhlak MJ, Liu X, Locasale JW, Huang J, Roychoudhuri R, Finkel T, Klebanoff CA, Restifo NP

A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell-like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8 T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.

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Science (New York, N.Y.), 363, 1095-9203, , 2019

PMID: 30923193

The Aire family expands.
Liston A, Dooley J

T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of identifies ILC3-like cells in the lymph nodes with similar properties.

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The Journal of experimental medicine, , 1540-9538, , 2019

PMID: 30923044

Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes.
Van Nieuwenhove E, Lagou V, Van Eyck L, Dooley J, Bodenhofer U, Roca C, Vandebergh M, Goris A, Humblet-Baron S, Wouters C, Liston A

Juvenile idiopathic arthritis (JIA) is the most common class of childhood rheumatic diseases, with distinct disease subsets that may have diverging pathophysiological origins. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed.

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Annals of the rheumatic diseases, , 1468-2060, , 2019

PMID: 30862608

Signalling circuits that direct early B-cell development.
Petkau G, Turner M

In mammals, the B-cell lineage arises from pluripotent progenitors in the bone marrow. During their development, B-cells undergo lineage specification and commitment, followed by expansion and selection. These processes are mediated by regulated changes in gene expression programmes, rearrangements of immunoglobulin (Ig) genes, and well-timed rounds of proliferation and apoptosis. Many of these processes are initiated by environmental factors including cytokines, chemokines, and cell-cell contacts. Developing B-cells process these environmental cues into stage-specific functions via signalling pathways including the PI3K, MAPK, or JAK-STAT pathway. The cytokines FLT3-Ligand and c-Kit-Ligand are important for the early expansion of the B-cell precursors at different developmental stages and conditions. Interleukin 7 is essential for commitment to the B-cell lineage and for orchestrating the Ig recombination machinery. After rearrangement of the immunoglobulin heavy chain, proliferation and apoptosis, and thus selection, are mediated by the clonal pre-B-cell receptor, and, following light chain rearrangement, by the B-cell receptor.

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The Biochemical journal, 476, 1470-8728, 769-778, 2019

PMID: 30842310

The transcription factor c-Myb regulates CD8 T cell stemness and antitumor immunity.
Gautam S, Fioravanti J, Zhu W, Le Gall JB, Brohawn P, Lacey NE, Hu J, Hocker JD, Hawk NV, Kapoor V, Telford WG, Gurusamy D, Yu Z, Bhandoola A, Xue HH, Roychoudhuri R, Higgs BW, Restifo NP, Bender TP, Ji Y, Gattinoni L

Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8 T cell memory compartment. Following viral infection, CD8 T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8 T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8 T cell stemness and highlight its therapeutic potential.

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Nature immunology, 20, 1529-2916, 337-349, 2019

PMID: 30778251

Open Access

Relative Frequencies of Alloantigen-Specific Helper CD4 T Cells and B Cells Determine Mode of Antibody-Mediated Allograft Rejection.
Alsughayyir J, Chhabra M, Qureshi MS, Mallik M, Ali JM, Gamper I, Moseley EL, Peacock S, Kosmoliaptsis V, Goddard MJ, Linterman MA, Motallebzadeh R, Pettigrew GJ

Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. Here, we examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR). An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient () C57BL/6 recipients against donor H-2K MHC class I alloantigen was provided by adoptively transferred "TCR75" CD4 T cells that recognize processed H-2K allopeptide via the indirect-pathway. Transfer of large numbers (5 × 10) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2K humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) recipients, suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to recipients resulted in eventual BALB/c heart allograft rejection (MST 20 days). Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c heart grafts were predominantly generated by extrafollicular foci: splenic germinal center (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of TCR75 CD4 T cells that are genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (10), although long-lasting, did not have a discernible extrafollicular component, and grafts were rejected much more slowly (MST 50 days). By modeling antibody responses to Hen Egg Lysozyme protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favors development of the extrafollicular response, whereas GC activity is favored by a relatively high ratio of B cells. In summary, a relative abundance of helper CD4 T cells favors development of strong extrafollicular alloantibody responses that mediate acute humoral rejection, without requirement for GC activity. This work is composed of two parts, of which this is Part I. Please read also Part II: Chhabra et al., 2019.

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Frontiers in immunology, 9, 1664-3224, 3039, 2018

PMID: 30740108

Open Access