Life Sciences Research for Lifelong Health


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

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. ( 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

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

Germinal Center Alloantibody Responses Mediate Progression of Chronic Allograft Injury.
Chhabra M, Alsughayyir J, Qureshi MS, Mallik M, Ali JM, Gamper I, Moseley EL, Peacock S, Kosmoliaptsis V, Goddard MJ, Linterman MA, Motallebzadeh R, Pettigrew GJ

Different profiles of alloantibody responses are observed in the clinic, with those that persist, often despite targeted treatment, associated with poorer long-term transplant outcomes. Although such responses would suggest an underlying germinal center (GC) response, the relationship to cellular events within the allospecific B cell population is unclear. Here we examine the contribution of germinal center (GC) humoral alloimmunity to chronic antibody mediated rejection (AMR). A murine model of chronic AMR was developed in which T cell deficient () C57BL/6 recipients were challenged with MHC-mismatched BALB/c heart allografts and T cell help provided by reconstituting with 10 "TCR75" CD4 T cells that recognize self-restricted allopeptide derived from the H-2K MHC class I alloantigen. Reconstituted recipients developed Ig-switched anti-K alloantibody responses that were slow to develop, but long-lived, with confocal immunofluorescence and flow cytometric characterization of responding H-2K-allospecific B cells confirming persistent splenic GC activity. This was associated with T follicular helper (T) cell differentiation of the transferred TCR75 CD4 T cells. Heart grafts developed progressive allograft vasculopathy, and were rejected chronically (MST 50 days), with explanted allografts displaying features of humoral vascular rejection. Critically, late alloantibody responses were abolished, and heart grafts survived indefinitely, in recipients reconstituted with TCR75 CD4 T cells that were genetically incapable of providing T cell function. The GC response was associated with affinity maturation of the anti-K alloantibody response, and its contribution to progression of allograft vasculopathy related principally to secretion of alloantibody, rather than to enhanced alloreactive T cell priming, because grafts survived long-term when B cells could present alloantigen, but not secrete alloantibody. Similarly, sera sampled at late time points from chronically-rejecting recipients induced more vigorous donor endothelial responses than sera sampled earlier after transplantation. In summary, our results suggest that chronic AMR and progression of allograft vasculopathy is dependent upon allospecific GC activity, with critical help provided by T cells. Clinical strategies that target the T cell subset may hold therapeutic potential. This work is composed of two parts, of which this is Part II. Please read also Part I: Alsughayyir et al., 2019.

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Frontiers in immunology, 9, 1664-3224, 3038, 2018

PMID: 30728823

Open Access

Type I interferon induces CXCL13 to support ectopic germinal center formation.
Denton AE, Innocentin S, Carr EJ, Bradford BM, Lafouresse F, Mabbott NA, Mörbe U, Ludewig B, Groom JR, Good-Jacobson KL, Linterman MA

Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.

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

PMID: 30723095

Data regarding transplant induced germinal center humoral autoimmunity.
Qureshi MS, Alsughayyir J, Chhabra M, Ali JM, Goddard MJ, Devine C, Conlon TM, Linterman MA, Motallebzadeh R, Pettigrew GJ

This data is related to the research article entitled "Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy" (Harper et al., 2016) [2]. The data presented here focuses on the humoral autoimmune response triggered by transferred allogeneic CD4 T cells and includes details on: (a) the recipient splenic germinal center (GC) response; (b) augmentation of humoral autoimmunity and accelerated heart allograft rejection following transplantation from donors primed against recipient; (c) flow cytometric analysis of donor and recipient CD4 T cells for signature markers of T follicular helper cell differentiation; (d) donor endothelial cell migration in response to column purified autoantibody from recipient sera; (e) analysis of development of humoral responses in recipients following adoptive transfer of donor CD4 T cells and; (f) the development of humoral autoimmunity in mixed haematopoietic chimeric mice.

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Data in brief, 22, 2352-3409, 647-657, 2019

PMID: 30671513

Open Access

Prospective study evaluating immune-mediated mechanisms and predisposing factors underlying persistent postinfectious abdominal complaints.
Florens MV, Van Wanrooy S, Dooley J, Aguilera-Lizarraga J, Vanbrabant W, Wouters MM, Van Oudenhove L, Peetermans WE, Liston A, Boeckxstaens GE

The role of persistent immune activation in postinfectious irritable bowel syndrome (PI-IBS) remains controversial. Here, we prospectively studied healthy subjects traveling to destinations with a high-risk to develop infectious gastroenteritis (IGE) in order to identify immune-mediated mechanisms and risk factors of PI-IBS.

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Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 31, 1365-2982, e13542, 2019

PMID: 30657233

IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis.
Humblet-Baron S, Franckaert D, Dooley J, Ailal F, Bousfiha A, Deswarte C, Oleaga-Quintas C, Casanova JL, Bustamante J, Liston A

Inflammatory activation of CD8 T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8 T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder.

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The Journal of allergy and clinical immunology, , 1097-6825, , 2018

PMID: 30578871

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology.
Schlenner S, Pasciuto E, Lagou V, Burton O, Prezzemolo T, Junius S, Roca CP, Seillet C, Louis C, Dooley J, Luong K, Van Nieuwenhove E, Wicks IP, Belz G, Humblet-Baron S, Wouters C, Liston A

is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans.

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Annals of the rheumatic diseases, 78, 1468-2060, 342-349, 2019

PMID: 30552177

Open Access

A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease.
Van Horebeek L, Hilven K, Mallants K, Van Nieuwenhuijze A, Kelkka T, Savola P, Mustjoki S, Schlenner SM, Liston A, Dubois B, Goris A

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate >55%. Validation in an independent dataset demonstrates excellent performance (sensitivity >57%, specificity >98%, replication rate >80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with nonsynonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher CADD and GERP scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.

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Human molecular genetics, , 1460-2083, , 2018

PMID: 30541027

Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy.
Qureshi MS, Alsughayyir J, Chhabra M, Ali JM, Goddard MJ, Devine C, Conlon TM, Linterman MA, Motallebzadeh R, Pettigrew GJ

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection. In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (T) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host T cell differentiation. Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host T cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of T cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.

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Journal of autoimmunity, , 1095-9157, , 2018

PMID: 30528910

The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly in myogenesis.
Bye-A-Jee H, Pugazhendhi D, Woodhouse S, Brien P, Watson R, Turner M, Pell J

Members of the ZFP36 family of RNA-binding proteins regulate gene expression post-transcriptionally by binding to AU-rich elements in the 3'UTR of mRNA and stimulating mRNA degradation. The proteins within this family target different transcripts in different tissues. In particular, ZFP36 targets myogenic transcripts and may have a role in adult muscle stem cell quiescence. Our study examined the requirement of ZFP36L1 and ZFP36L2 in adult muscle cell fate regulation.

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Skeletal muscle, 8, 2044-5040, 37, 2018

PMID: 30526691

Open Access

Biosynthesis of histone messenger RNA employs a specific 3' end endonuclease.
Pettinati I, Grzechnik P, Ribeiro de Almeida C, Brem J, McDonough MA, Dhir S, Proudfoot NJ, Schofield CJ

Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. We report cellular, genetic, biochemical, substrate selectivity, and crystallographic studies providing evidence that an additional endoribonuclease, MBL domain containing protein 1 (MBLAC1), is selective for 3' processing of RD histone pre-mRNA during the S-phase of the cell cycle. Depletion of MBLAC1 in cells significantly affects cell cycle progression thus identifying MBLAC1 as a new type of S-phase-specific cancer target.

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eLife, 7, 2050-084X, , 2018

PMID: 30507380

Open Access

Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence.
Nojima T, Tellier M, Foxwell J, Ribeiro de Almeida C, Tan-Wong SM, Dhir S, Dujardin G, Dhir A, Murphy S, Proudfoot NJ

Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNAs are generally short lived, length restricted, and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly, depletion of the ubiquitous Pol-II-associated transcription elongation factor SPT6 promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes, which correlates with increased lncRNA transcription. SPT6 knockdown also impairs the recruitment of the Integrator complex to chromatin, which results in a transcriptional termination defect for lncRNA genes. This leads to the formation of extended, polyadenylated lncRNAs that are both chromatin restricted and form increased levels of RNA:DNA hybrid (R-loops) that are associated with DNA damage. Additionally, these deregulated lncRNAs overlap with DNA replication origins leading to localized DNA replication stress and a cellular senescence phenotype. Overall, our results underline the importance of restricting lncRNA expression.

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Molecular cell, 72, 1097-4164, 970-984.e7, 2018

PMID: 30449723

Open Access

Regulation of the Germinal Center Response.
Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L

The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3 T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided.

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Frontiers in immunology, 9, 1664-3224, 2469, 2018

PMID: 30410492

Open Access

Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells.
Humblet-Baron S, Barber JS, Roca CP, Lenaerts A, Koni PA, Liston A

Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently, an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in murine studies with constitutive depletion of DCs, as well as in patients with congenital deficiency in DCs caused by mutations in or The mechanistic link between DC deficiency and MPD was not predicted through the known biology and has remained an enigma. Prevailing models suggest numerical DC deficiency leads to MPD through compensatory myeloid differentiation. Here, we formally tested whether MPD can also arise through a loss of DC function without numerical deficiency. Using mice whose DCs are deficient in antigen presentation, we find spontaneous MPD that is characterized by splenomegaly, neutrophilia, and extramedullary hematopoiesis, despite normal numbers of DCs. Disease development was dependent on loss of the MHC class II (MHCII) antigen-presenting complex on DCs and was eliminated in mice deficient in total lymphocytes. Mice lacking MHCII and CD4 T cells did not develop disease. Thus, MPD was paradoxically contingent on the presence of CD4 T cells and on a failure of DCs to activate CD4 T cells, trapping the cells in a naive Flt3 ligand-expressing state. These results identify a novel requirement for intercellular collaboration between DCs and CD4 T cells to regulate myeloid differentiation. Our findings support a new conceptual framework of DC biology in preventing MPD in mice and humans.

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Blood, 133, 1528-0020, 319-330, 2019

PMID: 30333120

Open Access

Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.
Lagou V, Garcia-Perez JE, Smets I, Van Horebeek L, Vandebergh M, Chen L, Mallants K, Prezzemolo T, Hilven K, Humblet-Baron S, Moisse M, Van Damme P, Boeckxstaens G, Bowness P, Dubois B, Dooley J, Liston A, Goris A

The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives.

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Cell reports, 25, 2211-1247, 798-810.e6, 2018

PMID: 30332657

Open Access

Mice Deficient in Nucleoporin Nup210 Develop Peripheral T Cell Alterations.
van Nieuwenhuijze A, Burton O, Lemaitre P, Denton AE, Cascalho A, Goodchild RE, Malengier-Devlies B, Cauwe B, Linterman MA, Humblet-Baron S, Liston A

The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.

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Frontiers in immunology, 9, 1664-3224, 2234, 2018

PMID: 30323813

Open Access

The Long Non-coding RNA Anticipates Foxp3 Expression in Regulatory T Cells.
Brajic A, Franckaert D, Burton O, Bornschein S, Calvanese AL, Demeyer S, Cools J, Dooley J, Schlenner S, Liston A

Mammalian genomes encode a plethora of long non-coding RNA (lncRNA). These transcripts are thought to regulate gene expression, influencing biological processes from development to pathology. Results from the few lncRNA that have been studied in the context of the immune system have highlighted potentially critical functions as network regulators. Here we explored the nature of the lncRNA transcriptome in regulatory T cells (Tregs), a subset of CD4 T cells required to establish and maintain immunological self-tolerance. The identified Treg lncRNA transcriptome showed distinct differences from that of non-regulatory CD4 T cells, with evidence of direct shaping of the lncRNA transcriptome by Foxp3, the master transcription factor driving the distinct mRNA profile of Tregs. Treg lncRNA changes were disproportionally reversed in the absence of Foxp3, with an enrichment for colocalisation with Foxp3 DNA binding sites, indicating a direct coordination of transcription by Foxp3 independent of the mRNA coordination function. We further identified a novel lncRNA , as a member of the core Treg lncRNA transcriptome. expression anticipates Foxp3 expression during Treg conversion, and -deficient mice show a mild delay in and peripheral Treg induction. These results implicate as part of the upstream cascade leading to Treg conversion, and may provide clues as to the nature of this process.

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Frontiers in immunology, 9, 1664-3224, 1989, 2018

PMID: 30319599

Open Access

Insufficient IL-10 Production as a Mechanism Underlying the Pathogenesis of Systemic Juvenile Idiopathic Arthritis.
Imbrechts M, Avau A, Vandenhaute J, Malengier-Devlies B, Put K, Mitera T, Berghmans N, Burton O, Junius S, Liston A, de Somer L, Wouters C, Matthys P

Systemic juvenile idiopathic arthritis (sJIA) is a childhood-onset immune disorder of unknown cause. One of the concepts is that the disease results from an inappropriate control of immune responses to an initially harmless trigger. In the current study, we investigated whether sJIA may be caused by defects in IL-10, a key cytokine in controlling inflammation. We used a translational approach, with an sJIA-like mouse model and sJIA patient samples. The sJIA mouse model relies on injection of CFA in IFN-γ-deficient BALB/c mice; corresponding wild type (WT) mice only develop a subtle and transient inflammatory reaction. Diseased IFN-γ-deficient mice showed a defective IL-10 production in CD4 regulatory T cells, CD19 B cells, and CD3CD122CD49b NK cells, with B cells as the major source of IL-10. In addition, neutralization of IL-10 in WT mice resulted in a chronic immune inflammatory disorder clinically and hematologically reminiscent of sJIA. In sJIA patients, IL-10 plasma levels were strikingly low as compared with proinflammatory mediators. Furthermore, CD19 B cells from sJIA patients showed a decreased IL-10 production, both ex vivo and after in vitro stimulation. In conclusion, IL-10 neutralization in CFA-challenged WT mice converts a transient inflammatory reaction into a chronic disease and represents an alternative model for sJIA in IFN-γ-competent mice. Cell-specific IL-10 defects were observed in sJIA mice and patients, together with an insufficient IL-10 production to counterbalance their proinflammatory cytokines. Our data indicate that a defective IL-10 production contributes to the pathogenesis of sJIA.

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Journal of immunology (Baltimore, Md. : 1950), 201, 1550-6606, 2654-2663, 2018

PMID: 30266771