LAG3 marks activated but hyporesponsive NK cells.

Vasilyeva, V.; Makinson, O.; Chan, C.; Park, M.; O'Dwyer, C.; Ali, A.; Abrar, U. H. K.; Tanese de Souza, C.; Hasim, M. S.; Asif, S.; Kurdieh, R.; Abou-Hamad, J.; Yakubovich, E.; Hodgins, J.; Al Haddad, P.; Pietropaolo, G.; Mazzei, J.; Seo, H.; Huang, Q.; Nersesian, S.; Chay, D.; Jacquelot, N.; Cook, D.; Lee, S.-H.; Sciume, G.; Waggoner, S. N.; Ardolino, M.; Marotel, M.

doi:10.1101/2024.12.18.629184

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.12.18.629184

LAG3 marks activated but hyporesponsive NK cells.

View original source ↗Export metadata ↓

Abstract

Natural Killer (NK) cells are critical for immunosurveillance yet become dysfunctional in contexts such as chronic stimulation by viral infections or cancer. This phenomenon is similar to T cell exhaustion but less well characterized, which limits therapeutic interventions. As shown for T cells, NK cells often display an increased expression of immune checkpoint proteins (ICP) following chronic stimulation, and ICP blockade therapies are currently being explored for several cancer types, which have remarkable patient benefits. Nevertheless, the nature of ICP expression in NK cells is still poorly documented. In this study, we aimed to identify the conditions that lead to and the phenotype of immune checkpoint LAG3 (Lymphocyte-activation gene 3) expressing NK cells. Using various experimental models, we found that LAG3 is expressed by murine NK cells upon activation in different contexts, including in response to cancer and acute viral infections. LAG3 marks a subset of immature, proliferating and activated cells, which, despite activation, have a reduced capacity to respond to a broad range of stimuli. Further characterization also revealed that LAG3+ NK cells exhibit a transcriptional signature similar to that of exhausted CD8+ T cells. Taken together, our results support the use of LAG3 as a marker of dysfunctional NK cells across diverse chronic and acute inflammatory conditions.

Source connections

Published article ↗

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Vasilyeva, V., Makinson, O., Chan, C., Park, M., O'Dwyer, C., Ali, A., Abrar, U. H. K., Tanese de Souza, C., Hasim, M. S., Asif, S., Kurdieh, R., Abou-Hamad, J., Yakubovich, E., Hodgins, J., Al Haddad, P., Pietropaolo, G., Mazzei, J., Seo, H., Huang, Q., Nersesian, S., Chay, D., Jacquelot, N., Cook, D., Lee, S.-H., Sciume, G., Waggoner, S. N., Ardolino, M., Marotel, M.. 2024-12-21. LAG3 marks activated but hyporesponsive NK cells.. https://doi.org/10.1101/2024.12.18.629184

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

ACE-engineered human iPSC-derived neutrophils enhance host defense against multidrug-resistant bacterial infections

Severe neutropenia predisposes patients to life-threatening infections, while donor-dependent granulocyte transfusions are limited by availability and variable cell quality. Here, we engineered human induced pluripotent stem cells (iPSCs) to constitutively or inducibly express angiotensin-converting enzyme (ACE) and differentiated them into functional ACE-engineered neutrophils (ACE-iNeu). ACE expression enhanced granulocytic maturation, reactive oxygen species generation, inflammatory cytokine production, and antimicrobial signaling. ACE-iNeu exhibited enhanced bactericidal activity against methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. Following adoptive transfer into neutropenic mice, ACE-iNeu significantly reduced circulating and tissue bacterial burdens. Integrated metabolomic and transcriptomic analyses revealed ACE-associated alterations in adenine nucleotide abundance and developmental and inflammatory pathways. Together, these findings establish ACE engineering as a strategy to enhance the production and antimicrobial function of human iPSC-derived neutrophils and support further preclinical development of engineered granulocyte therapies for severe drug-resistant infections.

immunology↗

bioRxiv2026

Tetravalent dengue mRNA vaccination orchestrates balanced four-serotype immunity with durable memory and protection in mice.

An effective dengue vaccine must establish durable immunity across four dengue virus (DENV) serotypes, evade antibody-dependent enhancement (ADE), and overcome immune imprinting from prior exposure. Here, we developed TetprM-E mRNA-LNP, a tetravalent vaccine comprising LNP-formulated nucleoside-modified mRNAs encoding DENV1-4 precursor membrane-envelope (prM-E) antigens, and evaluated its immunogenicity, durability, protection and breath across serotype-specific immune backgrounds. Three immunization strategies elicited neutralizing titers greater than 1:1500 against each serotype. Passive transfer of immune sera conferred 100% survival and reduced viremia after lethal DENV2 challenge in immunocompromised mice. Vaccination induced DENV envelope (env)-specific CD8+T cells and CD4-dependent germinal-center responses. DENV env-binding antibodies persisted for 34 weeks alongside DENV env-specific memory B cells. Vaccine-elicited sera showed no measurable in vitro ADE. Although monovalent priming initially biased antibody responses, TetprM-E mRNA-LNP vaccination broadened neutralization across DENV1-4 regardless of priming serotype. Together, TetprM-E mRNA-LNP elicits broad, durable, and protective immunity despite serologic constraints from pre-existing immunity.

immunology↗

bioRxiv2026

The antagonism of sex chromosomes and sex hormones dictates outcomes in Th17 cell-mediated central nervous system autoimmunity.

Biological sex traits are shaped by the combined effects of both sex hormones and chromosomes. How these factors interact in sex-related autoimmune diseases, such as multiple sclerosis (MS), has been a subject of intense recent interest. Here, using the Four Core Genotype (FCG) mouse model, in which these two variables can be disentangled, we describe an antagonism between sex hormones and chromosomes that potently influences outcomes in T helper 17 (Th17)-driven progressive central nervous system (CNS) autoimmunity. Male gonadal hormones dampen disease severity, irrespective of sex chromosome complement, by promoting a Wnt/{beta}-catenin signaling program associated with a homeostatic, non-pathogenic Th17 phenotype. By contrast, XY chromosomal complement exacerbates Th17 pathogenicity in a recipient sex-dependent manner; we identify the X-linked molecule SUV39H1 as an inhibitor of inflammatory Th17 cell function. Unexpectedly, we found that hormonally and chromosomally female FCG Th17 cells induced far more severe disease than WT female counterparts despite being genetically identical, pointing to a parental imprinting effect in dictating Th17 cell pathogenicity. These latter investigations uncovered Runx2, a transcription factor previously linked to developmental programs, as a novel negative regulator of the pathogenicity of Th17 cells. Together, our findings establish biological sex as a multilayered regulator of Th17 pathogenicity, revealing distinct and sometimes opposing contributions of hormones, chromosomes, and parental inheritance.

immunology↗