Biology subjects

Paust, S.

Publications and source records attributed to Paust, S..

9 recordsLinked to original sources

bioRxiv2026

CXCR6⁺ natural killer cell immunotherapy preserves CD4⁺ T helper cells in humanized mice

Human immunodeficiency virus (HIV) persists despite antiretroviral therapy because long-lived viral reservoirs are not eliminated, and ongoing or rebound infection contributes to progressive loss of CD4 T helper cells. Natural killer (NK) cells can acquire adaptive, antigen-experienced functions, including recall responses to HIV envelope protein, suggesting that defined NK-cell subsets may be therapeutically useful against HIV. Because HIV-responsive adaptive NK-cell activity is enriched among CXC chemokine receptor 6-positive (CXCR6) NK cells, we tested whether CXCR6 NK cells provide enhanced antiviral activity and CD4 T-cell protection compared with CXCR6- NK cells. In co-cultures with HIV-infected primary CD4 T cells, PBMC-derived CXCR6 and CXCR6- NK cells both reduced viral replication, but CXCR6 NK cells mediated significantly greater suppression. In HIV-infected humanized mice, weekly infusion of expanded PBMC-derived NK cells lowered plasma viral burden, with CXCR6 NK cells providing stronger preservation of circulating CD4 T cells and significant preservation of splenic CD4 T cells. HIV-Env vaccination further enriched NK cells with enhanced therapeutic activity. CXCR6 NK cells derived from HIV-Env-vaccinated humanized mice produced the strongest suppression of HIV replication and restored CD4 T-cell frequencies in blood and spleen to levels comparable to uninfected controls. Together, these findings identify CXCR6 NK cells as an HIV-responsive adaptive NK-cell subset that combines antiviral activity with preservation of CD4 T-cell immunity in vivo. These data support further development of CXCR6 NK-cell therapy as a vaccine-informed cellular immunotherapy strategy for HIV.

immunology↗

bioRxiv2026

Lifestyle intervention is associated with attenuation of ER stress/inflammation and enhancement of naive immune cell identity in older adults with metabolic disease

Chronic inflammation and cellular stress are hallmarks of aging, obesity, and type 2 diabetes (T2D), but whether these programs can be modulated by lifestyle intervention in late life, particularly in the presence of established metabolic disease, remain unknown. We profiled circulating immune cells from older adults with obesity and T2D (ages 66-83 years; n = 9) before and after a 6-month lifestyle intervention combining caloric restriction with exercise training. Participants showed substantial weight loss ([~]7%) alongside improvements in glycemic control, insulin sensitivity, and physical performance. Longitudinal single-cell transcriptomic and epigenomic profiling identified two major changes. First, intervention was associated with downregulation of inflammatory and endoplasmic reticulum (ER) stress transcriptional programs, with the most pronounced effects observed in CD14+ monocytes. DDIT3 (CHOP) was transcriptionally and epigenetically downregulated and its inferred regulatory network encompassed multiple inflammatory mediators. Second, naive CD4+ T, naive Treg, and naive B cells exhibited an upregulation of naive cell identity genes, with naiveness scores increasing after intervention, which declines with age in an independent healthy adult cohort. Together, these findings suggest that lifestyle intervention is associated with coordinated remodeling of both innate and adaptive immune compartments in older adults, revealing substantial plasticity of the aging immune system especially targeting ER stress, inflammation, and naive lymphocyte identity programs.

immunology↗

bioRxiv2025

CMV reshapes lymphoid immunity in aging: a single-cell atlas with predictive modeling

Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latency and becomes increasingly prevalent with age. We systematically characterized CMV-associated immune remodeling by analyzing six human cohorts (two newly built) using single-cell RNA sequencing, T cell receptor (TCR) sequencing, and flow cytometry. Beyond the well-known expansion of CD4/CD8 TEMRA, adaptive NK, and {gamma}{delta} T cells, CMV(+) adults exhibited increased frequencies of GZMK CD8 T cells and atypical B cells, alongside a reduction of CD56dim NK cells. Longitudinal profiling of an individual who seroconverted revealed rapid CMV-driven shifts in circulating immune cell frequencies. Single-cell TCR data analyzed using a large database of CMV-associated clones combined with predictive modelling (CMVerify), identified novel CMV-specific clonal expansions reproduced across two independent cohorts. In the CD8 lineage, CMV-specific clones were enriched in GZMK CD8 and CD8 TEMRA cells, while in the CD4 lineage, Th1 cells showed clonal expansion alongside CD4 TEMRA cells. This integrative study revealed how latent CMV alters the cellular and clonal landscape, defining GZMK CD8 and Th1 cells as newly recognized elements of response to CMV in humans.

immunology↗

bioRxiv2025

TRAIL-mediated PMN-MDSC depletion prevents CD4+ T cell loss in HIV-infectedhumanized mice

Myeloid-derived suppressor cells (MDSCs) are critical regulators of HIV immunity, but the mechanisms behind their expansion and value as a therapeutic target remain unclear. We investigated MDSC function in HIV using a humanized mouse model. Acute HIV-1 infection triggered the systemic expansion of polymorphonuclear MDSCs (PMN-MDSCs), with their frequency correlating positively with plasma viral load. Notably, PMN-MDSC expansion increased further when natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) were depleted, suggesting these immune cells restrain MDSC proliferation. We identified Tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-induced apoptosis as a regulatory mechanism, as MDSCs expressed high levels of TRAIL receptor 2 (R2), while NK cells and CTLs upregulated TRAIL expression during HIV infection. Treating HIV-1-infected mice with a TRAIL-R2 agonist significantly reduced MDSC levels to those of uninfected mice and significantly improved NK cell and CTL immune function. Crucially, in viremic humanized mice, the treatment prevented CD4+ T cell loss, a hallmark of HIV-1 pathogenesis and acquired immune deficiency syndrome (AIDS) progression. These findings reveal the therapeutic potential of targeting MDSC apoptosis to mitigate CD4+ T cell depletion and enhance HIV-specific immunity, offering a new clinical target to prevent AIDS and insights into MDSC- NK/CTL cross-regulation during HIV-1 infection.

immunology↗

bioRxiv2022

M2e-specific monoclonal antibody cocktails against influenza A virus are superior to individual monoclonal antibody treatments, universally effective, and viral escape mutant resistant

Influenza, a negative sense single-strand RNA virus of the genus Orthomyxoviridae, causes respiratory illness in humans and animals and significant morbidity and mortality worldwide. While exposure to a specific influenza A strain causes homologous protection, two immune-dominant influenza A virus (IAV)-encoded epitopes - Hemagglutinin (HA) and Neuraminidase (NA) - undergo antigenic shift and drift, resulting in IAVs to which humans lack pre-existing immunity. Without a universal vaccine or therapeutic agent, influenza virus infections will significantly threaten human health. The extracellular domain of the Matrix protein 2-ion channel (M2e) is an ideal antigenic target for a universal influenza therapy: it is highly conserved across influenza A serotypes, has a low mutation rate, and is essential for viral entry and replication. However, less than 20% of humans generate M2e-specific antibodies in response to IAV exposure, thus lacking the benefits of M2e-MAb-mediated immunity. To therapeutically address this deficit, we generated several non-neutralizing M2e-specific monoclonal antibodies (M2e-MAbs) with strong universal IAV treatment potential. Using three MAbs that bind to M2e differentially and competitively, we developed a low-dose M2e-MAb triple cocktail as an effective universal prophylactic and therapeutic agent. We identified the low-dose M2e-MAb triple cocktails optimal antibody-clone combination, isotype, minimum effective dosage, and administration time points in mouse models challenged with human and zoonotic BSL-2 and BSL-3 IAV strains, demonstrating its universal potential. Using the IgG2a isotype, which had proven most effective, we established Fc{gamma}RI, Fc{gamma}RIII, and Fc{gamma}RIV as required for M2e-MAb-mediated protection of IAV-challenged mice. Importantly, we established individual M2e-MAbs and the resulting triple cocktail as effective and viral escape mutant-resistant treatments in immunocompetent and immunodeficient mice. These unique qualities provide precedence for prioritizing our M2e-MAbs for therapeutic development. CONFLICT OF INTEREST STATEMENTSP serves on the scientific advisory board for Shoreline Biosciences, Qihan Biotechnology and is a Scientific Consultant for Qihan Biotechnology and the Genomics Institute of the Novartis Research Foundation. The remaining authors declare no competing interests.

immunology↗

bioRxiv2021

Hematopoietic stem and progenitor cells improve survival from sepsis by boosting immunomodulatory cells

New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for 1 in 5 deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A Streptococcus (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5-7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naive HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50-60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis.

immunology↗

bioRxiv2020

Alcohol dependence promotes systemic IFN-γ and IL-17 responses in mice

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. AUD is associated with a variety of physiological changes and is a substantial risk factor for numerous diseases. We aimed to characterize systemic alterations in immune responses using a mouse model of chronic intermittent alcohol exposure to induce alcohol dependence. We exposed mice to chronic intermittent ethanol vapor for 4 weeks and used multiparametric flow cytometry to analyze the expression of cytokines IFN-{gamma}, IL-4, IL-10, IL-12 and IL-17 by different immune cells in the blood, spleen and liver of alcohol dependent and non-dependent control mice. We found increases in IFN-{gamma} and IL-17 expression in a cell type- and organ-specific manner. Often, B cells and neutrophils are primary contributors to increased IFN-{gamma} and IL-17 levels while other cell types play a secondary role. We conclude that chronic alcohol exposure promotes systemic pro-inflammatory IFN-{gamma} and IL-17 responses in mice. These responses are likely important in the development of alcohol-related diseases, but further characterization is necessary to understand the initiation and effects of systemic inflammatory responses to chronic alcohol exposure.

immunology↗

bioRxiv2020

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

Existing patient-derived-xenograft (PDX) mouse models of solid tumors lack a fully tumor-donor matched "syngeneic" and functional immune system. We developed such a model by engrafting lymphopenic recipient mice with a fresh undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TIL) expanded in the recipient mice for several weeks. Tumors engrafted in about seventy to eighty percent of syngeneic-immune-system-PDX (SIS-PDX) mice, which harbored tumor-exhausted immune-effector and functional immune-regulatory cells persisting for at least six-months post-engraftment. Interleukin-15 (IL-15)-stimulation in addition to immune checkpoint inhibition (ICI), prevented resistance, resulting in complete or partial response to combined treatment. Further, the depletion of Cytotoxic T lymphocytes (CTLs) and/or Natural Killer (NK) cells from combined immunotherapy in SIS-PDX mice revealed that both cell types are required for the maximal response to tumor. Our novel SIS-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies designed to eradicate solid tumors.

immunology↗

bioRxiv2019

Human NK cell deficiency as a result of biallelic mutations in MCM10

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here we report a novel cause of NKD resulting from compound heterozygous mutations in MCM10 that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. By modeling MCM10 deficiency in human NK cell lines and primary NK cell precursors, we demonstrate that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function.

immunology↗