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bioRxiv2018

Targeting ion channel TRPM7 promotes the thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation

In BriefGenetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2R and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.\n\nHIGHLIGHTSO_LIIon channel TRPM7 controls Treg development\nC_LIO_LIThe deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the periphery\nC_LIO_LITRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activation\nC_LIO_LIInhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cells\nC_LI\n\nSUMMARYThe thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2R expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.

immunology↗

bioRxiv2018

Mice deficient in nucleoporin Nup210 develop peripheral T cell alterations

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.

immunology↗

bioRxiv2018

High-resolution genetic and phenotypic analysis of KIR2DL1 alleles and their association with pre-eclampsia

Killer-cell immunoglobulin-like receptor (KIR) genes are inherited as haplotypes, expressed by NK cells and linked to outcomes of infectious diseases and pregnancy. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. Here, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected both in peripheral blood and in uterine single NK cells. Using this new method, we demonstrate that both blood and uterine NK cells co-dominantly express KIR2DL1A and KIR2DL1B allotypes, but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that KIR2DL1A, not KIR2DL1B, associates with increased disease risk. This method will facilitate our understanding of how individual KIR2DL1 allelic variants affect NK cell function and contribute to disease risk.

immunology↗

bioRxiv2018

Susceptibility to Neutralization by Broadly Neutralizing Antibodies Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs

Efforts to HIV cure are obstructed by reservoirs of latently infected CD4+ T-cells that can re-establish viremia. Broadly neutralizing HIV-specific antibodies (bNAbs), defined by unusually high neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4+ T-cells has not been determined. Thus, the extent to which neutralization breadths and potencies can be used to infer the corresponding parameters of infected-cell binding is currently unknown. We assessed the breadths and potencies of bNAbs against 36 viruses reactivated from peripheral blood CD4+ T-cells of ARV-treated HIV-infected individuals, using paired neutralization and infected-cell binding assays. Single antibody breadths ranged from 0-64% for neutralization (IC80[≤]10g/ml) and 0-89% for binding, with two-antibody combinations reaching 0-83% and 50-100%, respectively. Infected-cell binding correlated with virus neutralization for 10 out of 14 antibodies (e.g. 3BNC117, r=0.87, p<0.0001). Heterogeneity was observed, however, with a lack of significant correlations for 2G12, CAP256.VRC26.25, 2F5, and 4E10. Our results provide guidance on the selection of bNAbs for interventional cure studies; both by providing a direct assessment of intra-and inter-individual variability in neutralization and infected cell binding in a novel cohort, and by defining the relationships between these parameters for a panel of bNAbs.\n\nImportanceAlthough anti-retroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their abilities to both prevent the infection of new cells (neutralization), and also to direct the killing of infected cells. We isolated 36 HIV strains from individuals whose virus was suppressed by medication, and tested 14 different antibodies for neutralization of these viruses and for binding to cells infected with the same viruses (critical for engaging natural killer cells). For both neutralization and infected-cell binding, we observed variation both between individuals, and amongst different viruses within an individual. For most antibodies, neutralization activity correlated with infected cell binding. These data provide guidance on the selection of antibodies for clinical trials.

immunology↗

bioRxiv2018

Removal of the C6 vaccinia virus interferon-β inhibitor in the hepatitis C vaccine candidate MVA-HCV elicited in mice high immunogenicity in spite of reduced host gene expression

Hepatitis C virus (HCV) represents a major global health problem for which a vaccine is not available. MVA-HCV is a unique HCV vaccine candidate based in the modified vaccinia virus Ankara (MVA) vector expressing the nearly full-length genome of HCV genotype 1a that elicits broad and polyfunctional CD8+ T-cell responses in mice. With the aim to improve the immune response of MVA-HCV and due to the importance of interferon (IFN) in HCV infection, we deleted in MVA-HCV the vaccinia virus (VACV) C6L gene, encoding an inhibitor of IFN-{beta} that prevents activation of the transcription factors IRF3 and IRF7. The resulting vaccine candidate (MVA-HCV {Delta}C6L) expresses all HCV antigens and deletion of C6L had no effect on viral growth in permissive chicken cells. In human monocyte-derived dendritic cells, infection with MVA-HCV {Delta}C6L triggered severe down-regulation of IFN-{beta}, IFN-{beta}-induced genes and cytokines similarly to MVA-HCV, as defined by real-time PCR and microarray analysis. In infected mice both vectors had a similar profile of recruited immune cells and induced comparable levels of adaptive and memory HCV-specific CD8+ T-cells, mainly against p7+NS2 and NS3 HCV proteins, with a T cell effector memory (TEM) phenotype. Furthermore, antibodies against E2 were also induced. Overall, our findings showed that while these vectors had a profound inhibitory effect on gene expression of the host, they strongly elicited CD8+ T cell and humoral responses against HCV antigens. These observations add support to the consideration of these vectors as potential vaccine candidates against HCV.\n\nIMPORTANCEHepatitis C virus represents a global health problem with 71 million of people infected worldwide. While direct-acting antivirals agents can cure hepatitis C virus infection in most of patients, their high cost and the emergence of drug resistant variants make them not a feasible and affordable strategy to eradicate the virus. Therefore, a vaccine is an urgent goal that requires efforts in understanding the correlates of protection for hepatitis C virus clearance. Poxvirus vectors, in particular the attenuated modified vaccinia virus Ankara, are ideal as vaccine candidates due to their ability to induce both T and B cell immune responses against heterologous antigens and protection against a wide spectrum of pathogens. Here we describe the generation, genetics and immunogenicity elicited by MVA-HCV {Delta}C6L, a novel vaccine candidate for hepatitis C virus that expresses nearly all of hepatitis C proteins but lacks an IFN-{beta} inhibitor, the C6 vaccinia virus protein.

immunology↗

bioRxiv2018

EROS is required for phagocyte NADPH oxidase function in humans and its deficiency causes Chronic Granulomatous Disease.

The phagocyte respiratory burst is mediated by the phagocyte NADPH oxidase, a multi-protein subunit complex that facilitates production of reactive oxygen species and which is essential for host defence. Monogenic deficiency of individual subunits leads to chronic granulomatous disease (CGD), which is characterized by an inability to make reactive oxygen species, leading to severe opportunistic infections and auto-inflammation. However, not all cases of CGD are due to mutations in previously identified subunits. We recently showed that Eros, a novel and highly conserved ER-resident transmembrane protein, is essential for the phagocyte respiratory burst in mice because it is required for expression of gp91phox-p22phox heterodimer, which are the membrane bound components of the phagocyte NADPH oxidase. We now show that the function of EROS is conserved in human cells and describe a case of CGD secondary to a homozygous EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of EROS in human immunity and describes a novel cause of CGD.\n\nClinical ImplicationsChronic granulomatous disease is caused by an inability to make reactive oxygen species via the phagocyte NADPH oxidase. Mutations in C17ORF62/EROS, which controls gp91phox- p22phox abundance, are a novel cause of chronic granulomatous disease.\n\nKey MessagesO_LIThe murine gene, Eros, is known to regulate abundance of gp91phox-p22phox heterodimer and Eros deficient mice are susceptible to infection\nC_LIO_LIWe show that the function of EROS is conserved in human cells and that a homozygous mutation in EROS causes chronic granulomatous disease\nC_LI

immunology↗

bioRxiv2018

Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

PU.1 is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later downregulated. Pioneering activity of PU.1 was tested in in this developmentally dynamic context, by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T cell development, and by using stage-specific gain and loss of function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborators, C/EBP factors. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative tradeoffs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At non-promoter sites PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at non-promoter sites where local chromatin accessibility depended on the presence of PU.1. Runx motifs and Runx1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without Runx1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition served by non-DNA binding domains of PU.1.

immunology↗

bioRxiv2018

Cryo-EM structure of the circumsporozoite protein of Plasmodium falciparum with a vaccine-elicited antibody reveals maturation of inter-antibody contacts

The circumsporozoite protein (CSP) on the surface of Plasmodium falciparum sporozoites is important for parasite development, motility, and host hepatocyte invasion. However, intrinsic disorder of the NANP repeat sequence in the central region of CSP has hindered its structural and functional characterization. Here, the cryo-EM structure at [~]3.4 [A] resolution of a recombinant shortened CSP construct (rsCSP) with the variable domains (Fabs) of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies. This unusual structure appears to be stabilized and/or induced by interaction with an antibody where contacts between adjacent Fabs are somatically mutated and enhance the interaction. Such maturation in non-antigen contact residues may be an effective mechanism for antibodies to target tandem repeat sequences and provide novel insights into malaria vaccine design.\n\nSummaryAn unusual spiral conformation is formed for the NANP repeat region in Plasmodium falciparum circumsporozoite protein (CSP) in complex with antibodies generated by the RTS,S vaccine and is stabilized by affinity-matured inter-Fab interactions.

immunology↗

bioRxiv2018

Osmolality controls the expression of cathelicidin antimicrobial peptide in human macrophages

An imbalance between extracellular and intracellular fluid osmolality causes osmotic stress and affects cellular homeostasis. Recent research suggests that osmotic stress is also associated with various innate and adaptive immune responses. Here we present the surprising finding that osmolality tightly controls the expression of cathelicidin antimicrobial peptide (CAMP) in human macrophages. CAMP expression is strongly upregulated under hyperosmotic conditions and downregulated under hypoosmotic conditions. We also provide evidence that this osmolality-mediated antimicrobial response is dependent on nuclear factor of activated T-cells 5 (NFAT5) and mitogen-activated protein kinase (MAPK) p38. Finally, Toll-like receptor (TLR) activation inhibits osmolality-mediated expression of CAMP in human macrophages, suggesting that this osmolality-dependent regulation of CAMP is more relevant under homeostatic conditions, rather than during acute infections. This study expands our knowledge of the regulation of human antimicrobial peptides and highlights osmolality as an important and independent factor shaping host innate immune homeostasis.

immunology↗

bioRxiv2018

Hepatitis B Virus Inhibits Neutrophil Extracellular Traps Release by Modulating Reactive Oxygen Species Production and Autophagy

Neutrophils, an important component of the innate immune system, release extracellular traps (NETs) to eliminate invaded pathogens by trapping and killing microbes. A dysfunctional innate immune response is a major cause of persistent hepatitis B virus (HBV) infection. HBV has been shown to reduce neutrophil responses. The objectives of the present study were to determine whether HBV influenced NETs release and to identify the underlying mechanisms. Primary neutrophils and circulating blood samples were collected from 40 patients with a chronic hepatitis B infection (CHB) and 40 healthy controls to detect NETs release using a Quant-iT Pico Green dsDNA assay and to determine the levels of HBV-DNA and HBV markers. NETs release was decreased in patients with a CHB infection, and hepatitis B surface antigen, hepatitis B e antigen and hepatitis B core antibody levels negatively correlated with NETs release. The Quant-iT Pico Green dsDNA assay and western blotting were used to examine the effect of HBV proteins (HBV X protein, HBV C protein, HBV E protein and HBV S protein) on NETs release in vitro. Based on the flow cytometry and western blot data, HBV C protein and HBV E protein inhibited NETs release by decreasing reactive oxygen species (ROS) production and autophagy. Overall, HBV may inhibit NETs release by modulating ROS production and autophagy to escape the immune system and promote the establishment of a chronic infection.

immunology↗

bioRxiv2018

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia of the developing brain have unique functional properties but how their activation states is regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain with multiple models of neuroinflammation-mediated injury and primary human microglia we found that a reduction in Wnt/{beta}-catenin signalling is necessary and sufficient to drive an oligodendrocyte-injurious microglial phenotype. We validated in a cohort of preterm born infants that genomic variation in the WNT pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a BBB penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

immunology↗

bioRxiv2018

Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

immunology↗

bioRxiv2018

TGFβ stimulates fibroblast-like synovial cells to produce ED-A fibronectin in osteoarthritis

IntroductionThe pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Wear and tear leads to tissue degradation and tissue repair responses, including tissue growth factor beta (TGF{beta})-induced myofibroblast production of extracellular matrix (ECM). Fibronectins are an essential part of the ECM, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Alternatively-spliced fibronectin contains the ED-A domain (ED-A FN) and has been shown to activate Toll-like receptor 4. In this study, we tested the hypothesis that FN fragments containing the ED-A domain could be one mechanism transducing mechanical events into inflammatory signals in OA.\n\nMethodsSamples of synovial membrane and cartilage were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A FN and the myofibroblast marker alpha smooth muscle actin (SMA) was performed on synovial membranes and fibroblast-like synovial cells (FLS). FLS were stimulated with TGF{beta}, TNF, lipopolysaccharide, IL-6, OA synovial fluid, or chondrocyte lysate, and analyzed for ED-A FN. Synovial cells isolated by enzymatic digestion and human monocyte-derived macrophages (MDM) were incubated with recombinant ED-A FN, plasmin, cellular FN, or cellular FN digested with plasmin; and culture supernatants were analyzed for MCP-1 and TNF.\n\nResultsWe hypothesized that ED-A FN is produced by OA FLS in response to factors found in the OA synovial joint. Indeed, the production of ED-A FN by OA FLS was increased by TGF{beta}, OA synovial fluid, and lysed chondrocytes in all experiments (n=3). ED-A FN co- localized with the myofibroblast marker SMA in both the OA FLS (n=3) and in the OA synovial membranes (n=8). We further hypothesized that ED-A FN expression is associated with cellular density and expression of inflammatory molecules in OA. ED-A FN staining was associated with both number of lining layer cells (rho=0.85 and p=0.011) and sublining cells (rho=0.88 and p=0.007) in the OA synovium (n=8), and co-localized with both MCP-1 and TNF (n=5). Recombinant ED-A FN increased the production of both MCP-1 and TNF by MDM (n=3) and OA FLS (n=3). Finally, we demonstrated that the FN fragments containing the ED-A domain generated the same production of both MCP-1 and TNF as recombinant ED-A FN.\n\nConclusionThe disease process in OA shares features with the chronic wound healing response including myofibroblast differentiation and production of mediators that promote myofibroblast production of ED-A FN. We show that recombinant and plasmin-derived ED-A fragments stimulate FLS and MDM to produce pro-inflammatory mediators. Our findings support utilizing ED-A FN for drug delivery or therapeutic targeting of the formation of ED- A FN or the enzymatic fragmentation of FN to reduce pro-inflammatory responses in OA.

immunology↗

bioRxiv2018

Peptide length distribution and multiple specificity in naturally presented HLA-I ligands

HLA-I molecules bind short peptides and present them for recognition by CD8+ T cells. The length of HLA-I ligands typically ranges from 8 to 12 amino acids, but variability is observed across different HLA-I alleles. Here we collected recent in-depth HLA peptidomics data, including 12 newly generated HLA peptidomes (31,896 unique peptides) from human meningioma samples, to analyze the peptide length distribution and multiple specificity across 84 different HLA-I alleles. We observed a clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to study the structural basis of peptide length distributions and predict peptide length distributions from HLA-I sequences. We further identified multiple specificity in several HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distribution and multiple specificity improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on the new human meningioma samples.

immunology↗

bioRxiv2018

Vasculature-associated adipose tissue macrophages dynamically adapt to inflammatory and metabolic challenges

Tissue-resident macrophages comprise the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophage populations change during metabolic stress and ageing, and are thought to contribute to the pathogenesis of obesity. Here, we studied adipose tissue macrophage subpopulations in the steady state, and in response to nutritional and infectious challenges.\n\nUsing comprehensive cell-surface-based and gene expression analyses, we found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying a very high endocytic capacity. We refer to these cells as Vasculature-associated Adipose tissue Macrophages (VAMs). Chronic high fat diet (HFD) feeding results in the accumulation of a monocyte-derived CD11c+CD64+ double positive (DP) macrophage eWAT population with a predominant anti-inflammatory gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that adipose tissue macrophage populations adapt to metabolic stress and inflammation, suggesting an important role for these cells in restoring homeostasis.

immunology↗

bioRxiv2018

Anti-V2 Antibody Deficiency in Individuals Infected With HIV-1

The positive correlation of high levels of plasma anti-V2 antibodies (Abs) with protective immunity in the Phase III anti-HIV RV144 vaccine trial generated interest in the induction of these Abs for HIV vaccine development. We analyzed plasma samples from 79 chronically infected Cameroonian individuals for Ab reactivity against three V1V2 fusion proteins and five cyclic V2 peptides and found that HIV-1 infection induces different levels of anti-V2 Abs. While the majority of plasma samples reacted strongly with one or more V2 antigens, 10% (8) of the samples were nonreactive. Deficiency of anti-V2 Abs was consistently found in longitudinal plasma samples tested over 8 to 54 months of HIV infection. There was a strong correlation between binding activities of plasma anti-V2 Abs and anti-gp120 and anti-gp41 Abs, suggesting that deficiency of V2 Abs could be related, in part, to a limited ability to elicit strong Ab responses. Analysis of gp120 sequences revealed that the V2 region of viruses from donors with V2-deficient versus V2-reactive Abs displayed a tendency toward longer length, more glycans, and lower isoelectric point and charge. No differences between these two patient groups were noted in the same parameters measured in the V1 region. These data suggest that immunogens containing a shorter V2 region with fewer glycosylation sites and higher electrostatic charges would be beneficial for induction of anti-V2 Abs, but the ability to mount a strong general Ab response to HIV-1 appears to be a dominant factor.\n\nIMPORTANCEThe results of the RV144 vaccine clinical trial showed a correlation between plasma Abs against a V1V2 fusion protein and a decreased risk of acquiring HIV-1 infection. This turned the focus of some HIV vaccine design to the induction of elevated levels of anti-V2 Abs to increase vaccine efficacy. In plasma samples from Cameroonian individuals infected with HIV-1, we observed broad variations in levels of anti-V2 Abs, and 8 of the 79 plasma samples tested displayed substantial deficiency of V2 Abs. Sequence analysis of the V2 region from plasma viruses and multivariate analyses of V2 characteristics showed a significant difference in several features between V2-deficient and V2-reactive plasma Abs. These results suggest that HIV vaccine immunogens containing a V2 region with shorter length, fewer glycosylation sites, and higher electrostatic charges may be beneficial for induction of a higher level of anti-V2 Abs and thus contribute to HIV vaccine efficacy.

immunology↗

bioRxiv2018

Single haplotype admixture models using large scale HLA genotype frequencies to reproduce human admixture

The Human Leukocyte Antigen (HLA) is the most polymorphic region in humans. Anthropologists use HLA to trace populations migration and evolution. However, recent admixture between populations masks the ancestral haplotype frequency distribution.\n\nWe present an HLA-based method based on high-resolution HLA haplotype frequencies to resolve population admixture using a non-negative matrix factorization formalism and validated using haplotype frequencies from 56 populations. The result is a minimal set of original populations decoding roughly 90% of the total variance in the studied admixtures. These original populations agree with the geographical distribution, phylogenies and recent admixture events of the studied groups.\n\nWith the growing population of multi-ethnic individuals, the matching process for stem-cell and solid organ transplants is becoming more challenging. The presented algorithm provides a framework that facilitates the breakdown of highly admixed populations into original groups, which can be used to better match the rapidly growing population of multi-ethnic individuals worldwide.\n\nAuthor SummaryHuman Leukocyte Antigen (HLA) is known to be the most polymorphic region in the human genome. Anthropologists frequently use HLA to trace migration and evolution of different populations. This is due to the high linkage among HLA genes leading to the transmission of intact haplotypes from parents to offspring, hence preserving key population ancestral features.\n\nWe developed a new HLA-based method to identify admixture models in mixed populations using high-resolution HLA haplotype frequencies. Our results highlight that a single highly polymorphic locus can contain enough information to map clearly human admixture and the population genetics of the different human populations, and reproduces results based on SNP arrays.\n\nThe presented algorithm is validated using haplotype frequencies sampled from 56 worldwide populations. Under such factorization we demonstrate that 90% of the variance in these populations can be explained using a much-reduced set of 8 ethnic groups. We demonstrate that the estimated ethnic groups and admixture models agree with the geographical distribution, population phylogenies and recent historic admixture events of the studied populations.

immunology↗

bioRxiv2018

Identification and Characterisation of the CD40-Ligand of Sigmodon hispidus

Cotton rats are an important animal model to study infectious diseases. They have demonstrated higher susceptibility to a wider variety of human pathogens than other rodents and are also the animal model of choice for pre-clinical evaluations of some vaccine candidates. However, the genome of cotton rats remains to be fully sequenced, with much fewer genes cloned and characterised compared to other rodent species. Here we report the cloning and characterization of CD40 ligand, whose human and murine counterparts are known to be expressed on a range of cell types including activated T cells and B cells, dendritic cells, granulocytes, macrophages and platelets and exerts a broad array of immune responses. The cDNA for cotton rat CD40L we isolated is comprised of 1104 nucleotides with an open reading frame (ORF) of 783bp coding for a 260 amino acid protein. The recombinant cotton rat CD40L protein was recognized by an antibody against mouse CD40L. Moreover, it demonstrated functional activities on immature bone marrow dendritic cells by upregulating surface maturation markers (CD40, CD54, CD80, and CD86), and increasing IL-6 gene and protein expression. The availability of CD40L gene identity could greatly facilitate mechanistic research on pathogen-induced-immunopathogenesis and vaccine-elicited immune responses.

immunology↗