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bioRxiv2024

Resolution of SARS-CoV-2 infection in human lung tissues is driven by extravascular CD163+ monocytes

While human autopsy samples have provided insights into pulmonary immune mechanisms associated with severe viral respiratory diseases, the mechanisms that contribute to a clinically favorable resolution of viral respiratory infections remain unclear due to the lack of proper experimental systems. Using mice co-engrafted with a genetically matched human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining successful resolution of SARS-CoV-2 infection in human lung tissues. Viral infection is rapidly cleared from fLX following a peak of viral replication, histopathological manifestations of lung disease and loss of AT2 program, as reported in human COVID-19 patients. Infection resolution is associated with the activation of a limited number of hematopoietic subsets, including inflammatory monocytes and non-canonical double-negative T-cells with cytotoxic functions, which are highly enriched in viral RNA and dissipate upon infection resolution. Activation of specific human fibroblast and endothelial subsets also elicit robust antiviral and monocyte chemotaxis signatures, respectively. Notably, systemic depletion of human CD4+ cells, but not CD3+ cells, abrogates infection resolution in fLX and induces persistent infection, supporting evidence that peripheral CD4+ monocytes are important contributors to SARS-CoV-2 infection resolution in lung tissues. Collectively, our findings unravel a comprehensive picture of the immunological events defining effective resolution of SARS-CoV-2 infection in human lung tissues, revealing markedly divergent immunological trajectories between resolving and fatal COVID-19 cases.

immunology↗

bioRxiv2024

45-Color Full Spectrum Flow Cytometry Panel for Deep Immunophenotyping of the Major Lineages Present in Human Peripheral Blood Mononuclear Cells with Emphasis on the T cell Memory Compartment.

The need for more in-depth exploration of the human immune system has moved the flow cytometry field forward with advances in instrumentation, reagent development and user-friendly implementations of data analysis methods. The increase in the number of markers evaluated simultaneously requires a careful selection of highly overlapping dyes to avoid introducing detrimental spread and compromising population resolution. In this manuscript, we present the strategy used in the development of a high-quality human 45-color panel which allows for comprehensive characterization of major cell lineages present in circulation including T cells, gamma delta T cells, NKT-like cells, B cells, NK cells, monocytes, basophils, dendritic cells, and ILCs, as well as more in-depth characterization of memory T cells. The steps taken to ensure that each marker in the panel was optimally resolved are discussed in detail. We highlight the outstanding discernment of cell activation, exhaustion, memory, and differentiation states of CD4+ and CD8+ T cells using this 45-color panel, enabling an in-depth description of very distinct phenotypes associated with the complexity of the T cell memory response. Furthermore, we present how this panel can be effectively used for cell sorting on instruments with a similar optical layout to achieve the same level of resolution. Functional evaluation of sorted specific rare cell subsets demonstrated significantly different patterns of immunological responses to stimulation, supporting functional and phenotypic differences within the T cell memory subsets. In summary, the combination of flow cytometry full spectrum technology, careful assay design and optimization, results in high resolution multiparametric assays. This approach offers the opportunity to fully characterize immunological profiles present in peripheral blood in the context of infectious diseases, autoimmunity, neurodegeneration, immunotherapy, and biomarker discovery. PURPOSE AND APPROPRIATE SAMPLE TYPESThis 45-color flow cytometry-based panel was developed as an expansion of the previously published OMIP-069 [1] and serves as an in-depth immunophenotyping of the major cell subsets present in human peripheral blood. The goal of this panel is to maximize the amount of high-quality data that can be acquired from a single sample, not only for more in-depth characterization of the immune system, but also to address the issue of limited sample availability. The panels development included identifying fluorochromes that could improve the performance of the original 40-color panel and expanding the number of markers for deeper delineation of memory status of T cell subpopulations. To increase the number of markers, it was critical that any expansion did not negatively impact the resolution and quality of the data. To achieve this, the fluorochrome combinations were carefully characterized to ensure optimal resolution of each marker. The panel allows for deep characterization of the major cell lineages present in circulation (CD4 T cells, CDS T cells, regulatory T cells, yo T cells, NKT-like cells, B cells, NK (Natural Killer) cells, monocytes, and dendritic cells), while also providing an in-depth characterization of the T cell compartment, with a combination of activation, inhibitory, exhaustion, and differentiation markers. The panel supports deep exploration of the memory status of CD4+ T cells, CDS+ T cells, and NKT-like cells. The steps taken in the optimization of the panel ensured outstanding resolution of each marker within the multicolor panel and unequivocal identification of each cell subset. This panel design and optimization will enhance the ability to characterize immunological profiles present in peripheral blood in the context of oncology, infectious diseases, autoimmunity, neurodegeneration, immunotherapy, and biomarker discovery. The panel was developed using fresh and cryopreserved human peripheral blood mononuclear cells (PBMCs) from healthy adults. We have not tested the panel on whole blood or biopsies; hence it is anticipated that the panel might require further optimization to be used with other sample types.

immunology↗

bioRxiv2024

Acidic pH attenuates immune killing through inactivation of perforin

Cytotoxic lymphocytes are pivotal effectors in our immune system. Their most potent way to delete virus infected or cancerous target cells is by perforin/granzyme dependent killing. Perforin is secreted into the immunological synapse and forms transmembrane pores in the target cell plasma membrane, allowing granzymes to enter the target cell cytosol and trigger apoptosis. The prowess of cytotoxic lymphocytes to efficiently eradicate target cells has been widely harnessed in immunotherapies against haematological cancers. Despite efforts to achieve a similar outcome against solid tumours, the immunosuppressive and acidic tumour microenvironment poses a persistent obstacle. Using different types of effector cells, including therapeutically relevant anti-CD19 CAR T cells, we demonstrate that the acidic pH typically found in solid tumours hinders the efficacy of immune therapies by impeding perforin pore formation within the immunological synapse. Nanometre-scale study of purified recombinant perforin undergoing oligomerization reveals that pore formation is inhibited specifically by preventing the formation of a transmembrane {beta}-barrel. The absence of perforin pore formation directly prevents target cell death. This finding uncovers a novel layer of immune effector inhibition that must be considered in the development of effective immunotherapies for solid tumours. One Sentence SummaryOur study reveals that an acidic environment hinders the efficacy of immune therapies by impeding the action of perforin, a critical protein in immune-mediated cell killing, directly within the immunological synapse.

immunology↗

bioRxiv2024

Discrimination of Jamaican fruit bat lymphocytes by flow cytometry

Bats are natural reservoir hosts of many important zoonotic viruses but because there are few immunological reagents and breeding colonies available for infectious disease research, little is known about their immune responses to infection. We established a breeding colony Jamaican fruit bats (Artibeus jamaicensis) to study bat virology and immunology. The species is used as a natural reservoir model for H18N11 influenza A virus, and as a surrogate model for SARS-CoV-2, MERS-CoV and Tacaribe virus. As part of our ongoing efforts to develop this model organism, we sought to identify commercially available monoclonal antibodies (mAb) for profiling Jamaican fruit bat lymphocytes. We identified several cross-reactive mAb that can be used to identify T and B cells; however, we were unable to identify mAb for three informative T cell markers, CD3{gamma}, CD4 and CD8. We targeted these markers for the generation of hybridomas, and identified several clones to each that can be used with flow cytometry and fluorescence microscopy. Specificity of the monoclonal antibodies was validated by sorting lymphocytes, followed by PCR identification of confirmatory transcripts. Spleens of Jamaican fruit bats possess about half the number of T cells than do human or mouse spleens, and we identified an unusual population of cells that expressed the B cell marker CD19 and the T cell marker CD3. The availability of these monoclonal antibodies will permit a more thorough examination of adaptive immune responses in Jamaican fruit bats that should help clarify how the bats control viral infections and without disease. ImportanceBats naturally host a number of viruses without disease, but which can cause significant disease in humans. Virtually nothing is known about adaptive immune responses in bats because of a lack of immunological tools to examine such responses. We have begun to address this deficiency by identifying several commercially available monoclonal antibodies to human and mouse antigens that are cross-reactive to Jamaican fruit bat lymphocyte orthologs. We also generated monoclonal antibodies to Jamaican fruit bat CD3{gamma}, CD4 and CD8 that are suitable for identifying T cell subsets by flow cytometry and immunofluorescent staining of fixed tissues. Together, these reagents will allow a more detailed examination of lymphocyte populations in Jamaican fruit bats.

immunology↗

bioRxiv2017

Deep Sequencing Reveals Transient Segregation of T Cell Repertoires in Splenic T Cell Zones During an Immune Response

Immunological differences between hosts, such as diverse T-cell receptor (TCR) repertoires, are widely credited for reducing the risk of pathogen spread and adaptation in a population. Within-host immunological diversity might likewise be important for robust pathogen control, but to what extent naive TCR repertoires differ across different locations in the same host is unclear. T-cell zones (TCZs) in secondary lymphoid organs provide secluded micro-environmental niches. By harboring distinct TCRs, such niches could enhance within-host immunological diversity. On the other hand, rapid T cell migration is expected to dilute such diversity. Here, we combined tissue micro-dissection and deep sequencing of the TCR {beta} chain to examine the extent to which TCR repertoires differ between TCZs in murine spleens. In the absence of antigen, we found little evidence for differences between different TCZs of the same spleen. Yet, three days after immunization with sheep red blood cells, we observed a >10-fold rise in the number of clones that appeared to localize to individual zones. Remarkably, these differences largely disappeared at 4 days after immunization, when hallmarks of an ongoing immune response were still observed. These data suggest that in the absence of antigen, any repertoire differences observed between TCZs of the same host can largely be attributed to random clone distribution. Upon antigen challenge, segregated TCR compartments appear and disappear within days. Such \"transient mosaic\" dynamics could be an important barrier for pathogen adaptation and spread during an immune response.

immunology↗

bioRxiv2018

Improved CD4 T-cell profile and inflammatory levels in HIV-infected subjects on maraviroc-containing therapy is associated with better responsiveness to HBV vaccination.

IntroductionWe previously found that a maraviroc-containing combined antiretroviral therapy (MVC-cART) was associated with a better response to the Hepatitis B Virus (HBV) vaccine in HIV-infected subjects younger than 50 years old. We aimed here to extend our previous analysis including immunological parameters related to inflammation, T-cell and dendritic cell (DC) subsets phenotype and to explore the impact of MVC-cART on these parameters.\n\nMethodsWe analyzed baseline samples of vaccinated subjects under 50 years old (n=41). We characterized CD4 T-cells according to the distribution of their maturational subsets and the expression of activation, senescence and prone-to-apoptosis markers; we also quantified Treg-cells and main DC subsets. Linear regressions were performed to determine the impact of these variables on the magnitude of vaccine response. Binary logistic regressions were explored to analyze the impact of MVC-cART on immunological parameters. Correlations with the time of MVC exposure were also explored.\n\nResultsMVC-cART remained independently associated with HBV-vaccine responsiveness even after adjusting by immunological variables. The %CD4+CD25hiFoxP3+ki67+ and %pDCs were also independently associated. Moreover, HIV-infected subjects on MVC-containing therapy prior to vaccination showed lower inflammatory levels, activated CD4 T-cells and frequency of Treg cells and higher frequency of recent thymic emigrants.\n\nConclusionTreg-cell levels negatively impacted the HBV-vaccine response, whereas higher pDCs levels and a MVC-cART prior to vaccination were associated with better responsiveness. These factors together with the improved phenotypic CD4 T-cell profile and the lower inflammatory levels found in subjects with a MVC-cART prior HBV vaccination could contribute to their enhanced vaccine response.

immunology↗

bioRxiv2018

Characterising antibody kinetics from multiple influenza infection and vaccination events in ferrets

The strength and breadth of an individuals antibody repertoire are important predictors of their response to influenza infection or vaccination. Although progress has been made in understanding qualitatively how repeated exposures shape the antibody mediated immune response, quantitative understanding remains limited. We developed a set of mathematical models describing short-term antibody kinetics following influenza infection or vaccination and fit them to haemagglutination inhibition (HI) titres from 5 groups of ferrets which were exposed to different combinations of trivalent inactivated influenza vaccine (TIV with or without adjuvant), priming inoculation with A/H3N2 and post-vaccination inoculation with A/H1N1. Based on the parameter estimates of the best supported model, we describe a number of key immunological features. We found quantifiable differences in the degree of homologous and cross-reactive antibody boosting elicited by different exposure types. Infection and adjuvanted vaccination generally resulted in strong, broadly reactive responses whereas unadjuvanted vaccination resulted in a weak, narrow response. We found that the order of exposure mattered: priming with A/H3N2 improved subsequent vaccine response, and the second dose of adjuvanted vaccination resulted in substantially greater antibody boosting than the first. Although there was considerable uncertainty in our estimates of antibody waning parameters, our results suggest that both short and long term waning were present and would be identifiable with a larger set of experiments. These results highlight the potential use of repeat exposure animal models in revealing short-term, strain-specific immune dynamics of influenza.\n\nAuthor summaryDespite most individuals having some preexisting immunity from past influenza infections and vaccinations, a significant proportion of the human population is infected with influenza each year. Predicting how an individuals antibody profile will change following exposure is therefore useful for evaluating which populations are at greatest risk and how effective vaccination strategies might be. However, interpretation of antibody data from humans is complicated by immunological interactions between all previous, unobserved exposures in an individuals life. We developed a mathematical model to describe short-term antibody kinetics that are important in building an individuals immune profile but are difficult to observe in human populations. We validated this model using antibody data from ferrets with known, varied infection and vaccination histories. We were able to quantify the independent contributions of various exposures and immunological mechanisms in generating observed antibody titres. These results suggest that data from experimental systems may be included in models of human antibody dynamics, which may improve predictions of vaccination strategy effectiveness and how population susceptibility changes over time.

immunology↗

bioRxiv2018

Interfacial actin protrusions mechanically potentiate killing by cytotoxic T cells

Cytotoxic T lymphocytes (CTLs) kill by forming immunological synapses with target cells and secreting toxic proteases and the pore forming protein perforin into the intercellular space. Immunological synapses are highly dynamic structures that potentiate perforin activity by applying mechanical force against the target cell. Here, we employed high-resolution imaging and microfabrication to investigate how CTLs exert synaptic forces and coordinate their mechanical output with perforin secretion. Using micropatterned stimulatory substrates that enable synapse growth in three dimensions, we found that perforin release occurs at the base of actin-rich protrusions that extend from central and intermediate locations within the synapse. These protrusions, which depended on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, were required for synaptic force exertion and efficient killing. They also mediated physical distortion of the target cell surface during CTL-target cell interactions. Our results reveal the mechanical basis of cellular cytotoxicity and highlight the functional importance of dynamic, three-dimensional architecture in immune cell-cell interfaces.\n\nOne sentence summaryCytotoxic T lymphocytes use F-actin-rich protrusions at the immunological synapse to potentiate perforin-and granzyme-mediated target cell killing.

immunology↗

bioRxiv2019

Immunogenomic landscape of hematological malignancies

Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. Here, we integrated over 8,000 transcriptomes and over 1,000 samples with multilevel genomic data of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival. Infiltration of cytotoxic immune cells was associated with distinct microenvironmental responses and driver alterations in different cancers, such as TP53 in acute myeloid leukemia and DTX1 in diffuse large B cell lymphoma. Epigenetic modification of CIITA regulating antigen presentation, cancer type-specific immune checkpoints such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity. Prognostic models highlighted the significance of immunological properties in predicting survival. Our study represents the most comprehensive effort to date to link immunology with cancer subtypes and genomics in hematological malignancies, providing a resource to guide future studies and immunotherapy development.

immunology↗

bioRxiv2019

Dissecting molecular regulatory mechanisms underlying noncoding susceptibility SNPs associated with 19 autoimmune diseases using multi-omics integrative analysis

The genome-wide association studies (GWAS) have identified hundreds of susceptibility loci associated with autoimmune diseases. However, over 90% of risk variants are located in the noncoding regions, leading to great challenges in deciphering the underlying causal functional variants/genes and biological mechanisms. Previous studies focused on developing new scoring method to prioritize functional/disease-relevant variants. However, they principally incorporated annotation data across all cells/tissues while omitted the cell-specific or context-specific regulation. Moreover, limited analyses were performed to dissect the detailed molecular regulatory circuits linking functional GWAS variants to disease etiology. Here we devised a new analysis frame that incorporate hundreds of immune cell-specific multi-omics data to prioritize functional noncoding susceptibility SNPs with gene targets and further dissect their downstream molecular mechanisms and clinical applications for 19 autoimmune diseases. Most prioritized SNPs have genetic associations with transcription factors (TFs) binding, histone modification or chromatin accessibility, indicating their allelic regulatory roles on target genes. Their target genes were significantly enriched in immunologically related pathways and other immunologically related functions. We also detected long-range regulation on 90.7% of target genes including 132 ones exclusively regulated by distal SNPs (eg, CD28, IL2RA), which involves several potential key TFs (eg, CTCF), suggesting the important roles of long-range chromatin interaction in autoimmune diseases. Moreover, we identified hundreds of known or predicted druggable genes, and predicted some new potential drug targets for several autoimmune diseases, including two genes (NFKB1, SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. In summary, our analyses may provide unique resource for future functional follow-up and drug application on autoimmune diseases, which are freely available at http://fngwas.online/. Author SummaryAutoimmune diseases are groups of complex immune system disorders with high prevalence rates and high heritabilities. Previous studies have unraveled thousands of SNPs associated with different autoimmune diseases. However, it remains largely unknown on the molecular mechanisms underlying these genetic associations. Striking, over 90% of risk SNPs are located in the noncoding region. By leveraging multiple immune cell-specific multi-omics data across genomic, epigenetic, transcriptomic and 3D chromatin interaction information, we systematically analyzed the functional variants/genes and biological mechanisms underlying genetic association on 19 autoimmune diseases. We found that most functional SNPs may affect target gene expression through altering transcription factors (TFs) binding, histone modification or chromatin accessibility. Most target genes had known immunological functions. We detected prevailing long-range chromatin interaction linking distal functional SNPs to target genes. We also identified many known drug targets and predicted some new drug target genes for several autoimmune diseases, suggesting their potential clinical applications. All analysis results and tools are available online, which may provide unique resource for future functional follow-up and drug application. Our study may help reduce the gap between traditional genetic findings and biological mechanistically exploration of disease etiologies as well as clinical drug development.

immunology↗

bioRxiv2026

Computational Convergence of Adaptive Immunity and Artificial Intelligence

The adaptive immune system and modern artificial intelligence (AI) have independently converged on identical computational strategies for solving the recognition and generalization problem: learning to identify which inputs should be associated with which outputs, such that performance extends to novel instances never seen during training. We demonstrate that four major AI architectural innovations can be derived from immunological first principles. Two represent exact mathematical equivalences: the softmax function in transformer attention is the Boltzmann distribution governing antibody-antigen binding; the InfoNCE loss in contrastive learning is the negative log of clonal selection probability. Two represent strategic convergences: the pre-training/fine-tuning/RLHF training hierarchy parallels the germline/somatic hypermutation/T follicular helper stages of antibody affinity maturation; retrieval-augmented generation mirrors the long-lived plasma cell and memory B cell dual memory system. Critically, these derivations run from immunology to AI, not the reverse--the mathematical structures of transformer attention and contrastive learning could have been derived from immunological first principles before their empirical discovery in AI. The framework generates testable predictions for immune specificity foundation models and suggests that certain computational strategies may be fundamental to any system solving recognition and generalization under resource constraints. Modern AI has independently converged on computational strategies that the adaptive immune system discovered through 500 million years of evolution. One-sentence summaryThe mathematics of transformer attention and contrastive learning can be derived from the biophysics of immune recognition.

immunology↗

bioRxiv2026

Mechanistic insights into B-cell activation and autoreactivity regulation in active SLE and remission.

ObjectiveTo define cellular and molecular mechanisms distinguishing active systemic lupus erythematosus (SLE) from remission by profiling autoreactive antinuclear antigen- positive (ANA+) and non-autoreactive B cells subsets in three cohorts: active disease (SLE-A), long-term, drug free remission (SLE-R), and healthy controls (HC). MethodsPeripheral blood B cells were phenotyped by flow cytometry, including ANA reactivity. Single-cell RNA sequencing (scRNA-seq) was performed on sorted ANA+ and ANA- subsets. ResultsSeven transcriptomic B cell clusters were resolved: quiescent (Naive 1, Marginal Zone B cells [MZB], IgG Memory 1) and activated (Age-Associated B cells [ABCs], Naive 2, IgM Memory, IgG Memory 2). SLE-A showed expansion of activated clusters, MZB contraction, and a higher IgG:IgM B cell ratio. SLE-R exhibited an "immunological reset," distinct from healthy homeostasis, with reduced ABCs and IgG Memory 2, persistence of Naive 2, and partial restoration of MZB and Naive 1. Interferon- (IFNa) signaling was elevated across clusters in SLE-A (SLE-A > SLE-R > HC), whereas TNF signaling was enriched in activated clusters across cohorts, with minimal differences between SLE-R and SLE-A. IFNa and TNF scores were inversely correlated. B cells predominantly expressed TNFR2, suggesting immunomodulatory TNF effects in remission. ANA+ cells in HC and SLE-R showed enriched Fc{gamma}RIIb inhibitory and IL-4/STAT6 signaling, suggesting reinstated regulatory control. DiscussionCompared to SLE-A, SLE-R was characterized by partial reversion to HC homeostasis with residual activation. These findings delineate immunologic features of remission and suggest therapeutic opportunities, including modulation of TNFR2, Fc{gamma}RIIb, and IL-4 to help sustain remission. What is already known on this topicSome patients with SLE achieve complete clinical remission without treatment, referred as immune reset; the mechanisms that underlie this state have not been well characterized. Healthy individuals and patients with Systemic Lupus Erythematosus (SLE) normally harbor similar frequencies of autoreactive B cells; the checkpoints that regulate activation of these cells are not fully defined. What this study addsB cells, stratified by their reactivity to nuclear antigens (ANA), from active SLE (SLE-A), drug-free remission (SLE-R), and healthy controls (HC) were analyzed using single cell sequencing and flow cytometry. We identified B cells states associated with disease activity; SLE-R displayed a distinct profile that differed from SLE-A and HC. TNF signaling was present in activated B cell subsets in SLE-A and SLE-R. This persistence in SLE-R may reflect an immunomodulatory function of TNF on TNFR2, which is expressed on B cells. ANA+ cells in SLE-R and HC were enriched for inhibitory Fc{gamma}RIIb and IL-4/STAT6 programs. How this study might affect research, practice or policyThe signatures identified help define the "immunological reset" state in patients with SLE-R. We also identified pathways, such as type I IFN, TNFR2, Fc{gamma}RIIb, IL-4/STAT6 as potential targets for maintaining remission.

immunology↗

bioRxiv2026

Microfilaremic loiasis is associated with T cell hyporesponsiveness against SARS CoV-2

BackgroundLoiasis is a chronic filarial infection endemic to Central and West Africa. Although long considered benign, increasing evidence links loiasis to substantial morbidity and mortality. The infection is associated with immune modulation, including Th2-skewed responses and elevated regulatory cytokines. Clinically, loiasis is classified as microfilaremic (presence of circulating microfilariae) or amicrofilaremic ("occult") disease, the latter defined by a history of eyeworm migration without detectable microfilaremia. This study investigated how chronic L. loa infection influences antibody and T cell responses to SARS-CoV-2 following natural infection. MethodsBetween 2022 and 2024 this cross-sectional study was done in Lambarene and surrounding rural areas of Gabon. Study procedures included diagnostics for loiasis and immunological assays. Microfilaremia was confirmed by stained blood smear microscopy, and occult disease was identified using the Rapid Assessment Procedure for Loiasis. SARS-CoV-2-specific IgG responses to spike and nucleocapsid proteins were measured by ELISA, and IFN-{gamma} responses to spike antigen were assessed using an interferon-gamma release assay. ResultsOverall, 192 participants were categorized as microfilaremic (n=43), occult loiasis (n=59), or without evidence of active loiasis (n=90). IFN-{gamma} responses were reduced in microfilaremic individuals compared with other participants (p= 0.031), whereas IgG responses did not differ. Subsequent analysis across the three groups confirmed that IFN-{gamma} responses were lower in microfilaremic compared with occult participants (p= 0.012). ConclusionThese findings suggest that microfilaremic loiasis may impair proinflammatory T cell responses to viral antigens, highlighting the need for further research into the broader immunological effects of Loa loa infection in endemic populations. Authors summaryLoiasis is a parasitic infection caused by the worm Loa loa and is common in parts of Central and West Africa. Although long considered relatively benign, growing evidence indicates that loiasis is associated with substantial morbidity. The immunological consequences of chronic Loa loa infection remain poorly understood. A small number of studies suggest that Loa loa may influence immune regulation, but its broader impact on antiviral immunity is largely unknown. The COVID-19 pandemic provided a unique opportunity to examine immune responses to a newly emerging virus in a population where loiasis is endemic. We therefore investigated how different forms of Loa loa infection influence immune responses after natural SARS-CoV-2 infection. We compared individuals with circulating microfilariae in their blood (microfilaremic), individuals with occult loiasis (history of eye worm), and individuals without signs of active infection. We found that microfilaremic individuals had weaker virus-specific IFN-{gamma} T cell responses, while antibody levels were similar across groups. These findings suggest that active loiasis may dampen certain antiviral immune functions. Understanding the underlying mechanisms is important, as such immune modulation could affect responses to vaccines and other infectious diseases in endemic regions.

immunology↗

bioRxiv2026

T-cell repertoire response in individuals with post-acute sequelae of COVID-19

T-cells are central to SARS-CoV-2 clearance and immunological memory, yet their contribution to the persistence of post-acute sequelae of COVID-19 (PASC) remains poorly understood. The immunological features that distinguish individuals who develop PASC from those who recover fully are unresolved, in part due to the phenotypic heterogeneity of the condition and the likely multiplicity of its underlying mechanisms. Here, we profiled longitudinal bulk TCR{beta} repertoires from 120 individuals in the INCOV cohort-71 with PASC and 49 without-sampled at two to three time points spanning the acute and post-acute phases of infection. Using robust statistical modeling of repertoire composition and clonal dynamics, we found that global statistics such as V, J gene usage and CDR3 length do not differ between groups, but that locally enriched sequence motifs and differentially dynamic clones reveal distinct T-cell signatures associated with PASC status. Clones contracting following the peak of the acute response were significantly enriched for SARS-CoV-2 specificity in both groups. Interestingly, Influenza A-specific TCRs were disproportionately enriched among contracting clones in PASC+ repertoires, implicating viral co-infection as a potential contributor to early disease severity and, possibly, PASC pathogenesis. Rare public TCR clones were markedly enriched for SARS-CoV-2 specificity, with PASC+ individuals harboring a modestly but significantly higher proportion than PASC- individuals. Together, we identified over 1,000 candidate TCR{beta} receptors potentially discriminating PASC+ from PASC- immune responses, opening a path toward the identification of disease-relevant T-cell specificities and the development of T-cell-based immunological biomarkers for long COVID.

immunology↗

bioRxiv2026

Cesium-137 and X-Ray Irradiation Yield Comparable Immune Phenotypes and Activation States in Bone Marrow Chimeric Studies

Bone marrow chimeras are widely used to study immune development and function. As the field moves from cesium-137 (137Cs)-based irradiators to X-ray irradiators for safety reasons, it is essential to determine if there are differences in immune system reconstitution after irradiating mice with one of these two radiation sources. Here, we performed a comprehensive immunological comparison of mice lethally irradiated with 137Cs or one of two different X-ray platforms and reconstituted with congenic bone marrow. Mice received 12 Gy total body radiation in two 6 Gy sessions followed by intravenous transfer of donor hematopoietic stem cells and were analyzed eight weeks post-transplant. We assessed mouse survival, donor chimerism, immune cell subset distribution, and activation states across multiple organs (bone marrow, spleen, lymph nodes, liver, and lung). All groups exhibited comparable survival and high levels of donor chimerism, with expected organ-specific reconstitution patterns. Immune lineage distributions, CD4/CD8 ratios, and activation states did not differ by irradiation type. Host-derived radioresistant cells were also similar across all irradiation groups and were predominantly composed of T cells skewed toward an activated phenotype. Overall, our data show that X-ray irradiation with proper filters and energy levels (225 KVp and 320 KVp) can yield equivalent immunological outcomes, including immune reconstitution and activation states, as compared to the same radiation dose from 137Cs-based irradiation in bone marrow chimera models. These results support the continued adoption of X-ray irradiation systems in place of 137Cs for generating bone marrow chimeras to be used across a wide range of immunologic studies.

immunology↗

bioRxiv2016

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

The outcome of Mycobacterium tuberculosis (Mtb) infection and the immunological response to the Bacille Calmette Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation on BCG efficacy has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individuals, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly-diverse inbred mouse strains, consisting of the founders and recombinant progeny of the \"Collaborative Cross\". Unlike natural populations, the structure of this panel allows the serial evaluation of genetically-identical individuals and quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects; the animals displayed a broad range of Mtb susceptibility, varied in their immunological response to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. Mtb susceptibility varied between lines, from extreme sensitivity to progressive Mtb clearance. Similarly, only a minority of the genotypes was protected by vaccination. BCG efficacy was genetically separable from susceptibility, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy, and provide a new resource to rationally develop more broadly efficacious vaccines.\n\nImportance: Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly-efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition to BCG efficacy. We found that the ability of BCG to protect an individual genotype was remarkably variable. BCG efficacy did not depend on the intrinsic susceptibility of the animal, but instead correlated with qualitative differences in the immune response to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provides a model system to develop interventions that will be useful in genetically diverse populations.

Microbiology↗

bioRxiv2020

Structural basis for variable IgE reactivities of Cor a 1 hazelnut allergens

A major proportion of allergic reactions to hazelnuts (Corylus avellana) are caused by immunologic cross-reactivity of IgE antibodies to pathogenesis-related class 10 (PR-10) proteins. Intriguingly, the four known isoforms of the hazelnut PR-10 allergen Cor a 1, denoted as Cor a 1.0401-Cor a 1.0404, share sequence identities exceeding 97 % but possess different immunologic properties. In this work we describe the NMR solution structures of these proteins and provide an in-depth study of their biophysical properties. Despite sharing highly similar three-dimensional structures, the four isoforms exhibit remarkable differences regarding structural flexibility, hydrogen bonding and thermal stability. Our experimental data reveal an inverse correlation between structural flexibility and IgE-binding, with the most flexible isoform having the lowest IgE-binding potential, while the isoform with the most rigid backbone scaffold displays the highest immunologic reactivity. These results point towards a significant entropic contribution to the process of antibody binding.

molecular biology↗

bioRxiv2020

Phospholipid Metabolism Is Associated with HIV Rebound Upon Treatment Interruption

Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from the plasma of 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load setpoints post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the pro-inflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral setpoints upon ART cessation. Furthermore, higher pre-ATI levels of the pro-inflammatory byproduct of intestinal lysophosphatidylcholine metabolism, trimethylamine-N-oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4+ T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible pro-inflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during- and post-ART warrants further investigation. IMPORTANCEThe likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a function of the interplay between the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that modulate these reservoirs. There is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the pro-inflammatory lysophosphatidylcholine and its intestinal metabolic byproduct, trimethylamine-N-oxide, and both faster time-to-viral rebound and higher viral load setpoint post ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during- and post-ART.

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