Biology subjects

Nakandakari-Higa, S.

Publications and source records attributed to Nakandakari-Higa, S..

6 recordsLinked to original sources

bioRxiv2026

Eosinophil-epithelial interactions mediate protective intestinal remodeling during food allergy

Food allergies are associated with progressive gastrointestinal symptoms driven by exacerbated mucosal type-2 immunity. Here, we investigated whether cellular interactions between the gut epithelium and innate immune cells regulate the severity of allergic symptoms in mice. Using the BALB/c OVA-alum food allergy model, we observed that repeated oral allergen challenges remodel the gut epithelium, expanding tuft cells, while shifting the intestinal stem cell niche toward a fetal-like repair state. Using uLIPSTIC, we systematically characterized in vivo immune-epithelial interactions and found that eosinophils and mast cells directly interact with intestinal epithelial cells (iECs) in an allergen challenge-dependent manner. Epithelial subset-specific uLIPSTIC provided further resolution and revealed that eosinophils and mast cells contact enteroendocrine cells and Paneth cells in a regionally compartmentalized manner. Allergic challenge was associated with rapid eosinophil migration towards the crypts and modulation of iEC differentiation. Depletion of eosinophils using two independent approaches reversed key markers of food allergy-associated epithelial remodeling, while exacerbating allergic diarrhea and mortality from anaphylactic shock. These findings establish eosinophils as orchestrators of protective epithelial remodeling in food allergies.

immunology↗

bioRxiv2026

Immune cells adapt to distinct stem cell niches to govern tissue homeostasis

Summary ParagraphIn adult tissues, epithelial stem cells exist within distinct residences, each endowing them with exclusive instructions for regenerative fitness under homeostasis and stress. Key components of these niches are immune cells, which classically protect the host against external and internal threats. Whether and how stem cell:immune cell crosstalk contributes to normal tissue biology remains less clear. Here, we discover functional adaptation of resident lymphocytes within two distinct skin stem cell niches and show that through this communication, each niche adjusts to meet diverse tissue demands. In the upper hair follicle, where microbial load is high, T cells express lymphotoxin-{beta} and stimulate adjacent receptor-positive epithelial stem cells to form an immune-competent niche that controls microbial expansion. By contrast, in the epidermis, these T cells produce amphiregulin to maintain continuous stem cell reconstitution of the skins barrier. Concomitantly, they express the immune checkpoint protein LAG-3, which autorestricts lymphocyte numbers, and hence amphiregulin levels, thereby preventing over-proliferative responses. Finally, when epidermal T cells are absent, dermal lymphocytes restore the imbalance by colonizing and adapting to their new niche. Our findings unveil functional specialization and homeostatic resilience of immune-stem cell niches, each tailored to suit the demands of distinct tissue microenvironments.

immunology↗

bioRxiv2023

Universal recording of cell-cell contacts in vivo for interaction-based transcriptomics

Cellular interactions are essential for tissue organization and functionality. In particular, immune cells rely on direct and usually transient interactions with other immune and non-immune populations to specify and regulate their function. To study these "kiss-and-run" interactions directly in vivo, we previously developed LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts), an approach that uses enzymatic transfer of a labeled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ helper T cells and antigen presenting cells, however. Here, we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the cellular partners of regulatory T cells in steady state, and identify germinal center (GC)-resident T follicular helper (Tfh) cells based on their ability to interact cognately with GC B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalog of the immune populations that physically interact with intestinal epithelial cells (IECs) and find evidence of stepwise acquisition of the ability to interact with IECs as CD4+ T cells adapt to residence in the intestinal tissue. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.

immunology↗

bioRxiv2022

Identification of dendritic cell-T cell interactions driving immune responses to food

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Dendritic cells (DCs) orchestrate these immune responses by presenting luminal antigens and inducing functional differentiation of CD4+ T cells into regulatory (pTreg) or pro-inflammatory (Th) subsets. However, the exact nature of the DCs inducing tolerance or inflammation to dietary antigens has been difficult to define. Using an intestine-adapted Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC) combined with single-cell transcriptomics, we characterized DCs presenting dietary antigens in the context of tolerance or infection. At steady-state, migratory cDC1 and cDC2 DCs, but not resident DCs, were found to present dietary antigen to cognate CD4+ T cells. Whereas cDC2s promoted T cell activation, only cDC1s induced their differentiation into pTregs. Infection with the helminth Strongyloides venezuelensis abrogated cDC1 presentation of dietary antigens, preventing pTreg and oral tolerance induction. In contrast, Heligmosomoides polygyrus infection only partially affected cDC1s, allowing oral tolerance to be maintained. An expanded population of cDC2s that induced type-2 immunity during both helminth infections did not present dietary antigens, demonstrating that compartmentalized presentation of luminal antigens can prevent food-specific Th2 responses during inflammatory conditions. Our data uncover novel cellular mechanisms by which tolerance to food is induced and can be disrupted during infections.

immunology↗

bioRxiv2022

Proximity-dependent labeling identifies dendritic cells that prime the antitumor CD4+ T cell response

Dendritic cells (DCs) are uniquely capable of transporting tumoral antigens to tumor-draining lymph nodes (tdLNs), and also interact with effector T cells within the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identify individual DCs capable of presenting antigen to CD4+ T cells in the tdLN as well as inside the tumor microenvironment (TME). Our findings reveal that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both within tumors and in the tdLN, and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation within the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.

immunology↗

bioRxiv2022

Human anti-ACE2 monoclonal antibodies as pan-sarbecovirus prophylactic agents

Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Here, we describe the development of human monoclonal antibodies that bind the ACE2 receptor rather than the viral spike protein. These antibodies block infection by all ACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants. Structural and biochemical analyses revealed that the antibodies target an ACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit ACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology and protect human ACE2 knock-in mice against SARS-CoV-2 infection. Such antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as ACE2-binding sarbecoviruses that might emerge as future pandemic threats.

microbiology↗