SEARCH · Search bioRxiv

Results for “Immunology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources

bioRxiv2017

HIV persistence during antiviral therapy occurs due to cellular proliferation

Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been attributed to viral replication in an ART sanctuary and long-lived and1or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a \"fossil record\" of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure.

immunology↗

bioRxiv2017

The integrated stress response pathway activates 4E-BP to bias mRNA translation and boost antimicrobial peptide synthesis in response to bacterial infection

Pathogenic bacterial infection imposes considerable cellular stress on the host and often leads to attenuation of mRNA translation. In this translation-suppressive environment, it is unclear how the host synthesizes various antimicrobial peptides (AMPs) to mount innate immune response. Here, we use Drosophila as a model to demonstrate that AMP production during infection relies on a translation bias mechanism mediated by the inhibitor of cap-dependent translation 4E-BP (Drosophila Thor), and the AMP 5UTRs that can undergo cap-independent translation. We found that 4E-BP is induced upon infection with the pathogenic bacteria Ecc15 by the stress-responsive transcription factor ATF4, and its upstream kinase GCN2. Moreover, loss of gcn2, atf4 or 4e-bp compromised immunity against Ecc15. In 4E-BP mutants, the transcriptional induction of AMPs after infection was unaffected, while the protein levels of AMPs were substantially reduced in their hemolymph. Analysis of the 5UTRs of AMPs using cell-based bicistronic reporters and in vitro translation analysis indicated that AMPs are translated in a cap-independent mechanism. Analysis of bicistronic reporters in the presence of 4E-BP indicate that infection enhances cap-independent translational activity associated with AMP 5UTRs, accounting for enhanced AMP translation during infection.\n\nHighlights O_LI4E-BP is transcriptionally induced by GCN2/ATF signaling in response to bacterial infection\nC_LIO_LI4E-BP mutants show unaltered antimicrobial peptide (AMP) transcript levels, but have reduced AMP translation\nC_LIO_LIAMP 5UTRs are translated cap-independently\nC_LIO_LITranslation bias by 4E-BP drives cap-independent AMP translation\nC_LI

immunology↗

bioRxiv2017

Intracellular BH3 profiling reveals shifts in anti-apoptotic dependency in B-cell maturation and activation

Apoptosis is critical to B-cell maturation, but studies of apoptotic regulation in primary human B cells is lacking. Previously, we found that infecting human B cells with Epstein-Barr virus induces two different survival strategies (Price et al., 2017). Here, we sought to better understand the mechanisms of apoptotic regulation in normal and activated B cells. Using intracellular BH3 profiling (iBH3), we defined the Bcl2-dependency of B-cell subsets from human peripheral blood and tonsillar lymphoid tissue as well as mitogen-activated B cells. We found that naive and memory B cells were BCL-2 dependent, while germinal center B cells were MCL-1 dependent and plasma cells were BCL-XL dependent. Proliferating B cells activated by CpG or CD40L/IL-4 became more dependent upon MCL-1 and BCL-XL. As B-cell lymphomas often rely on survival mechanisms derived from normal and activated B cells, these findings offer new insight into potential therapeutic strategies for lymphomas.

immunology↗

bioRxiv2017

Strain-Specific Human Natural Killer Cell Recognition of Influenza A Virus

AbstractInnate Natural killer (NK) cells employ an array of surface receptors to detect altered self induced by infection or malignancy. Despite their decisive role in early antiviral immunity, the cellular mechanisms governing if or how they discriminate between viral infections remain unresolved. Here, we demonstrate that while human NK cells are capable of reducing infection levels of distinct influenza A strains, the A/California/07/2009 (pH1N1) strain induces a significantly more robust IFN-{gamma} response than A/Victoria/361/2011 (H3N2) and all other strains tested. This surprising degree of strain specificity results in part from the inability of the pH1N1 strain to downregulate the activating ligands CD112 (Nectin-2) and CD54 (ICAM-1) as efficiently as the H3N2 strain, leading to enhanced NK cell detection and IFN-{gamma} secretion. A network analysis of differentially expressed transcripts identifies the interferon /{beta} receptor (IFNAR) pathway as an additional, critical determinant of this strain-specific response. Strain-specific downregulation of NK cell activating ligands and modulation of type I IFN production represents a previously unrecognized influenza immunoevasion tactic and could present new opportunities to modulate the quality and quantity of the innate antiviral response for therapeutic benefit.\n\nOne Sentence SummaryHuman natural killer cells distinguish between Influenza A strains using a combinatorial cytokine priming and receptor-ligand signaling mechanism.

immunology↗

bioRxiv2017

Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection

Intestinal intraepithelial lymphocytes (IELs) are located at the critical interface between the intestinal lumen, which is chronically exposed to food and microbes, and the core of the body. Using high-resolution microscopy techniques and intersectional genetic tools, we investigated the nature of IEL responses to luminal microbes. We observed that TCR{gamma}{delta} IELs exhibit distinct location and movement patterns in the epithelial compartment that were microbiota-dependent and quickly altered upon enteric infections. These infection-induced changes included increased inter-epithelial cell (EC) scanning, anti-microbial gene expression and glycolysis. Direct modulation of glycolysis was sufficient to change {gamma}{delta} IEL behavior and susceptibility to early pathogen invasion. Both {gamma}{delta} IEL behavioral and metabolic changes were dependent on EC pathogen sensing. Our results uncover a coordinated EC-IEL response to enteric infections that modulates lymphocyte energy utilization and dynamics and supports maintenance of the intestinal epithelial barrier.

immunology↗

bioRxiv2017

TCR-peptide contact profile determines immunogenicity in pathogen/tumor-derived MHC-I epitopes

The existence of population-wide T cell immunity is widely recognized for multiple pathogen-derived immunodominant epitopes, despite the vast diversity and individualized nature of T cell receptor (TCR) repertoire. We thus hypothesized that population-wide epitope immunogenicity could be probabilistically defined by exploiting public TCR features. To gain a proof-of-concept, here we describe a machine learning framework yielding probabilistic estimates of immunogenicity, termed \"immunogenicity scores\", by utilizing features designed to mimic thermodynamic interactions between peptides bound to major histocompatibility complex (MHC) and TCR repertoire. Immunogenicity score dynamics among observed and computationally simulated single amino acid mutants delineated the landscape of position- and residue-specific mutational impacts, and even quantitatively estimated escaping potentials of known epitopes with remarkable positional specificity. This study illustrates that the population-wide aspect of adaptive immunity is predictable via non-individualized approach, possibly indicating antigen-guided convergence of human T cell reactivity.

immunology↗

bioRxiv2017

Aging-associated dysbiosis increases susceptibility to enteric viral infection in Drosophila

Age is associated with increased susceptibility to enteric infections, but the molecular mechanisms are unclear. We find that aged Drosophila are more susceptible to enteric viral infections and that this increase in susceptibility is due to the aged microbiota, since depletion of the microbiota or reconstitution with a young microbiome suppressed infection. Metagenomic analysis of the aged microbiome revealed dysbiosis with an increased abundance in reactive oxygen species (ROS) producing pathways. This aged microbiota drives intestinal ROS production and we could restore immune function in old flies by reducing ROS genetically or pharmacologically. Moreover, we found that reconstitution of old flies with a cocktail of commensals, including L. fructivorans and heat-killed A. pomorum, could fully restore immunity. Altogether, these findings provide a mechanistic link between age-dependent dysbiosis and antiviral immunity and show that we can restore innate protection in aged animals, suggesting that this is a treatable and reversible state.

immunology↗

bioRxiv2017

Ruxolitinib partially reverses functional NK cell deficiency in patients with STAT1 gain-of-function mutations

BackgroundNatural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility.\n\nObjectiveWe sought to investigate NK cell function in STAT1 GOF patients. Methods: NK cell phenotype and function were determined in 16 STAT1 GOF patients.\n\nMethodsNK cell phenotype and function were determined in 16 STAT1 GOF patients.NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib.\n\nResultsPeripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT signaling with the small molecule JAK1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function.\n\nConclusionsProperly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of elevated STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

immunology↗

bioRxiv2017

Decreased intra-lymphocyte cytokines measurement in septic shock patients: a proof of concept study in whole blood

Functional testing protocols are thought to be the gold standard for the exploration of the immune system. However, in terms of routine analysis, they present numerous drawbacks and consequently their use is mainly limited to research applications. In the clinical context of septic shock, characterized by marked lymphocyte alterations, a new approach for lymphocyte intracellular cytokine measurement in whole blood upon was evaluated in a proof-of-concept study. Following lymphocyte activation, simultaneous intracellular labeling of Interferon-{gamma} (IFN-{gamma}), Tumor Necrosis Factor- (TNF-), and Interleukin-2 (IL-2) was performed in CD4+ and CD8+ T cells (identified by surface marking). The analysis was carried out by flow cytometry (6 colors). Results obtained in septic patients (n = 22) were compared to those of healthy volunteers (n = 8). Independently of lymphopenia, there were significant differences between groups. In particular there was significant decrease in the production of IL-2 and TNF- in septic patients, while the production of IFN-{gamma} was not significantly altered. Polyfunctional results showed that patients presented with increased percentages of triple negative lymphocytes. In contrast, volunteers had higher proportions of triple positive cells. The approach could be performed in a robust and consistent way, taking 4.5 hours to complete. Moreover, clear differences could be observed between clinical groups with this modified method. These characteristics illustrate the potential of this novel whole blood protocol for clinical applications. However, further research is required to determine the applicability compared to alternative test and to evaluate clinical performances in larger cohorts of patients.

immunology↗

bioRxiv2017

CD18-mediated adhesion is required for lung inflammation induced by mononuclear cell-derived extracellular vesicles

Extracellular vesicles are submicron vesicles that upregulate the synthesis of proinflammatory mediators by lung epithelial cells.\n\nWe investigated whether these structures adhere to lung epithelial cells, and whether adhesion is a prerequisite for their proinflammatory activity.\n\nExtracellular vesicles were generated by stimulation of normal human mononuclear cells with the calcium ionophore A23187, and labelled with carboxyfluorescein diacetate succinimidyl ester. Adhesion of vesicles to monolayers of immortalized bronchial epithelial cells (16HBE) and alveolar cells (A549) was analysed by fluorescence microscopy. The role of candidate adhesion receptors was evaluated with inhibitory monoclonal antibodies and soluble peptides. The synthesis of proinflammatory mediators was assessed by ELISA.\n\nTransmission electron microscopy confirmed the generation of closed vesicles with an approximate size range between 50 and 600 nm. Adhesion of extracellular vesicles to epithelial cells was minimal in baseline conditions and was upregulated upon stimulation of the latter with tumour necrosis factor-. Adhesion was blocked by an anti-CD18 antibody and by peptides containing the sequence RGD. The same molecules also blocked the upregulation of the synthesis of interleukin-8 and monocyte chemotactic protein-1 induced by extracellular vesicles.\n\nSummary statementExtracellular vesicles upregulate the synthesis of proinflammatory mediators by lung epithelial cells. CD18-mediated adhesion to target cells is required for this proinflammatory effect and might represent a target for anti-inflammatory therapy.

immunology↗

bioRxiv2017

Diverse Streptococcus pneumoniae strains drive a MAIT cell response through MR1-dependent and cytokine-driven pathways

Mucosal Associated Invariant T (MAIT) cells represent an innate T cell population of emerging significance. These abundant cells can recognize ligands generated by microbes utilizing the riboflavin synthesis pathway, presented via the major histocompatibility complex (MHC) class I-related molecule MR1 and binding of specific T cell receptors (TCR). They also possess an innate functional programme allowing microbial sensing in a cytokine-dependent, TCR-independent manner. Streptococcus pneumoniae is a major human pathogen that is also associated with commensal carriage, thus host control at the mucosal interface is critical. The recognition of S. pneumoniae strains by MAIT cells has not been defined, nor have the genomics and transcriptomics of the riboflavin operon (Rib genes). We examined the expression of Rib genes in S. pneumoniae at rest and in response to metabolic stress and linked this to MAIT cell activation in vitro. We observed robust recognition of S. pneumoniae strains at rest and following stress, using both TCR-dependent and TCR-independent pathways. The pathway used was highly dependent on the antigen-presenting cell, but was maintained across a wide range of clinically-relevant strains. The riboflavin operon was highly conserved across a range of 571 S. pneumoniae from 39 countries dating back to 1916, and different versions of the riboflavin operon were also identified in related Streptococcus species. These data indicate an important functional relationship between MAIT cells and S. pneumoniae,which may be tuned by local factors, including the metabolic state of the organism and the antigen-presenting cell that it encounters.\n\nAuthor SummaryStreptococcus pneumoniae is the leading cause of bacterial pneumonia, causes invasive diseases such as meningitis and bacteraemia, and is associated with significant morbidity and mortality, particularly in children and the elderly. Here, we demonstrate that a novel T cell population called Mucosal-associated invariant T (MAIT) cells is able to respond to a diverse range of S. pneumoniae strains. We found that this response was dependent on the T cell receptor (which recognises metabolites of the bacterial riboflavin biosynthesis pathway), cytokines, and the type of antigen-presenting cell. A population genomics approach was also used to assess the prevalence and diversity of the genes encoding the riboflavin biosynthesis pathway among a large and diverse collection of S. pneumoniae. These genes were highly conserved across a range of 571 S. pneumoniae from 39 countries dating back to 1916, and was also present in other related Streptococcus species. Given the low levels of MAIT cells in neonates and MAIT cell decline in the elderly, both of whom are at the highest risk of invasive pneumococcal disease, further understanding of the functional role of MAIT cells in host defense against this major pathogen may allow novel therapeutics or vaccines to be designed.

immunology↗

bioRxiv2017

Using mathematical modeling to define kinetic properties of HIV-specific CD8+ T-cell responses

Multiple lines of evidence indicate that CD8+ T cells are important in the control of HIV-1 (HIV) replication. However, CD8+ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8+ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8+ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8+ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8+ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8+ T cells in the chronic infection. The breadth of HIV-specific CD8+ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8+ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8+ T-cell responses and the presence of intra- and interclonal competition between multiple CD8+ T-cell responses; such competition may limit the magnitude of CD8+ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8+ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.\n\nAbbreviations

immunology↗

bioRxiv2017

Accurate Immune Repertoire Sequencing Reveals Malaria Infection Driven Antibody Lineage Diversification in Young Children

Accurately measuring antibody repertoire sequence composition in a small amount of blood is challenging yet important to the understanding of the repertoire response to infections and vaccinations. Here, we describe an accurate and high-coverage repertoire sequencing method, MIDCIRS, which uses as few as 1,000 naive B cells. Using it, we studied age-related antibody repertoire development and diversification before and during acute malaria in infants (< 12 months old) and toddlers (12 - 47 months old) with 4-8 ml of blood draws. Unexpectedly, we discovered high levels of somatic hypermutation (SHM) in infants as young as three months old. Antibody clonal lineage analysis revealed that both infants and toddlers increase SHM levels upon infection and memory B cells isolated from pre-malaria samples in malaria-experienced individuals continue to induce SHMs upon malaria rechallenge. These results highlight the vast potential of antibody repertoire diversification in infants and toddlers that has not been realized previously.

immunology↗

bioRxiv2017

Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age

Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. With age, however, they produce a myeloid-biased output that may lead to poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA-seq, we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is much more common amongst aged LT-HSCs and is uniquely primed to respond to acute inflammatory challenge. We predict several transcription factors to regulate differentially expressed genes between mLT-HSCs and other LT-HSC subsets. Among these, we show that Klf5, Ikzf1 and Stat3 play important roles in age-related inflammatory myeloid bias. These factors may regulate myeloid versus lymphoid balance with age, and can potentially mitigate the long-term deleterious effects of inflammation that lead to hematopoietic pathologies.\n\nHighlightsO_LILT-HSCs from young and aged mice have differential responses to acute inflammatory challenge.\nC_LIO_LIHSPCs directly sense inflammatory stimuli in vitro and have a robust transcriptional response.\nC_LIO_LIAged LT-HSCs demonstrate a cell-intrinsic myeloid bias during inflammatory challenge.\nC_LIO_LISingle-cell RNA-seq unmasked the existence of two subsets within the LT-HSC population that was apparent upon stimulation but not steady-state. One of the LT-HSC subsets is more prevalent in young and the other in aged mice.\nC_LIO_LIKlf5, Ikzf1 and Stat3 regulate age- and inflammation-related LT-HSC myeloid-bias.\nC_LI\n\nOne sentence summaryMurine hematopoietic stem cells display transcriptional heterogeneity that is quantitatively altered with age and leads to the age-dependent myeloid bias evident after inflammatory challenge.

immunology↗

bioRxiv2017

A mathematical model relates intracellular TLR4 oscillations to sepsis progression

Oscillations drive many biological processes and their modulation is determinant for various pathologies. In sepsis syndrome, Toll-like receptor 4 (TLR4) is a key sensor for signaling the presence of Gram-negative bacteria. Its expression and activity, along with its intracellular trafficking rates shift the equilibrium between the pro- and anti-inflammatory downstream signaling cascades, leading to either the physiological resolution of the bacterial stimulation or to sepsis. We hypothesize that the initial tlr4 expression in patients diagnosed with sepsis and TLR4 dynamic concentration changes on the cell membrane or intracellularly, dictates how the sepsis syndrome is initiated. Using a set of three differential equations, we defined the TLR4 flux between relevant cell organelles. We obtained three different regions in the phase space: 1. a limit-cycle describing unstimulated physiological oscillations, 2. a fixed-point attractor resulting from moderate LPS stimulation that is resolved and 3. a double-attractor resulting from sustained LPS stimulation that leads to sepsis. We tested the models against hospital data of sepsis patients and we correctly evaluate the clinical outcome of these patients.

immunology↗

bioRxiv2017

RhlR, but not RhlI, allows P. aeruginosa bacteria to evade Drosophila Tep4- mediated opsonization

When Drosophila flies feed on Pseudomonas aeruginosa strain PA14, some bacteria cross the intestinal barrier and start proliferating inside the hemocoel. This process is limited by hemocytes through phagocytosis. We have previously shown that the PA14 quorum-sensing regulator RhlR is required for these bacteria to elude the cellular immune response. RhlI synthesizes the auto-inducer signal that activates RhlR. Here, we compare the null mutant phenotypes of rhlR and rhlI in a variety of infection assays in Drosophila and in the nematode Caenorhabditis elegans. Surprisingly, in Drosophila, unlike{Delta} rhlR mutants,{Delta} rhlI mutants are only modestly attenuated for virulence and are poorly phagocytosed and opsonized in a Thioester-containing Protein4-dependent manner. Likewise, {Delta}rhlI but not {Delta}rhlR mutants colonize the digestive tract of C. elegans and kill it as efficiently as wild-type PA14. Thus, RhlR has an RhlI-independent function in eluding detection or counter-acting the action of the immune system. In contrast to the intestinal infection model, Tep4 mutant flies are more resistant to PA14 in a septic injury model, which also depends on rhlR. Thus, the Tep4 putative opsonin can either be protective or detrimental to host defense depending on the infection route.

immunology↗

bioRxiv2017

ISG15 induces IL-10 production in human monocytes and is a biomarker of disease severity during active tuberculosis

Interferon stimulated gene 15 (ISG15) deficiency in humans leads to severe interferonopathies and mycobacterial disease, the latter being previously associated to its extracellular cytokine-like activity. Here, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to human primary monocytes. Employing ex vivo systems analysis of human transcriptome datasets, we observed a significant correlation of ISG15-induced monocyte IL-10 and lymphocyte IFN{gamma} balanced expression. This effect was associated with p38 MAPK and PI3K signalling in healthy volunteers. The specificity and MAPK/PI3K-dependence of ISG15-induced monocyte IL-10 production was confirmed in vitro using CRISPR/Cas9 knockout and pharmacological inhibitors. Moreover, this ISG15/IL10 axis was amplified in leprosy but disrupted in human active tuberculosis (TB) patients. Importantly, ISG15 strongly correlated with inflammation and disease severity during active TB. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB, revealing a potential biomarker for disease severity in this major human disease.

immunology↗

bioRxiv2017

Maternal obesity alters uterine NK cell activity through a functional KIR2DL1/S1 imbalance

In pregnancy, uterine natural killer cells (uNK) play essential roles in coordinating uterine angiogenesis, blood vessel remodeling, and promoting maternal tolerance to fetal tissue. Deviances from a normal uterine microenvironment are thought to modify uNK function(s), limiting their ability to establish a healthy pregnancy. While maternal obesity has become a major health concern due to associations with adverse effects on fetal and maternal health, our understanding into how obesity contributes to poor pregnancy disorders is essentially unknown. Given the importance of uNK in pregnancy, this study sets out to examine if obesity affects uNK function. Using a cohort of pregnant women, we show that baseline activity of uNK from obese women is elevated, but that enhanced activity does not equate to increased killing potential. Instead, obesity associates with altered uNK production of angiogenic VEGF-A and PlGF. These changes coincide with alterations in NKp46+ and NKG2A+ uNK subsets and elevated expression of KIR2D(L1/S1/S3/S5) receptors. Detailed examination revealed that obesity leads to imbalances in KIR2DL1/S1 expression that together instruct altered responses to HLA-C2 antigen, including increased production of TNF. Together, these findings suggest that maternal obesity modulates uNK function by altering angiokine/cytokine production and the response to HLA-C2 antigen.

immunology↗