bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.02.18.431426

Brain endothelial CXCL12 attracts protective Natural Killer cells during ischemic stroke

Wang, S.·de Fabritus, L.·Ashok Kumar, P.·Werner, Y.·Siret, C.·Simic, M.·Kerdiles, Y. M.·Stumm, R.·van de Pavert, S. A.
View original source ↗Export metadata ↓

Abstract

Innate lymphoid cells (ILCs) have a function in homeostasis and immune responses, but their role in ischemic brain insult is unknown. Here, we report that ILCs are not resident within the mouse brain parenchyma during steady-state conditions, but are attracted after ischemic stroke. Specifically, we identified NK cells, ILC1s, ILC2s and ILC3s within the lesion, the highest influx being observed for NK cells and ILC1s. We further show that Cxcl12 expressed at the blood-brain barrier is essential for NK cells and NKp46+ ILC3s to migrate toward the lesion. Complementary, Cxcr4-deficiency in NK cells prevented NK cells from entering the infarct area. The lack of NK cell migration resulted in a higher neurological deficit in the beam-walk sensorimotor test. Our data show a new role for blood-brain barrier-derived Cxcl12 in attracting protective NK cells to ischemic brain lesions and identifies a new Cxcl12/ Cxcr4-mediated component of the innate immune response to stroke.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Wang, S., de Fabritus, L., Ashok Kumar, P., Werner, Y., Siret, C., Simic, M., Kerdiles, Y. M., Stumm, R., van de Pavert, S. A.. 2021-02-18. Brain endothelial CXCL12 attracts protective Natural Killer cells during ischemic stroke. https://doi.org/10.1101/2021.02.18.431426

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Ksp37 is a rapidly mobilized NK cell secretory protein that engages FGF2

A key feature of natural killer (NK) cells is their preloaded arsenal of effector molecules, allowing them to rapidly respond upon activation. In this study, we characterized a previously unexplored secretory protein, termed killer-specific secretory protein of 37 kDa (Ksp37), which is highly abundant in differentiated CD56dim NK cells. Ksp37 is rapidly secreted in a dose-dependent and JAK-1 dependent manner upon low levels of cytokine stimulation, making it a sensitive readout for NK cell activation. Following secretion, intracellular levels were rapidly replenished, preserving responsiveness to subsequent cytokine stimulation. We found that Ksp37 is stored in polarized intracellular compartments distinct from those containing canonical cytotoxic effector molecules, including granzyme B and perforin, which require stronger stimulation for release. Lastly, we identified Ksp37 as a novel binding partner of fibroblast growth factor 2 (FGF2). This opens new avenues of exploration for the role of NK cells in remodeling their extracellular environment by modulating the FGF2-FGFR1 axis, which plays a key role in tumor growth, angiogenesis and tissue repair.

immunology↗
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↗