Richard A. Flavell

A reporter mouse model to map RIG-I expression and function in vivo

The cytosolic RNA sensor RIG-I is a critical component of the innate immune response to RNA viruses, yet few tools exist to track RIG-I in vivo. Herein, we report the development of a RIG-I reporter mouse, termed RIG-ImScar, that enables fluorescence imaging and tractable immunoprecipitation of RIG-I in vivo. These mice revealed enrichment of RIG-I expression in circulatory, lymphoid, and mucosal tissues and broad expression across immune cell types. RIG-I itself is upregulated in response to IFN. To distinguish RIG-I sentinel cells, which are programmed to express RIG-I at steady state, from IFN-responder cells, we crossed RIG-ImScar mice with Mx1GFP mice. Blocking IFNAR with a monoclonal antibody showed that basal RIG-I expression in immune cells was largely independent of type I IFN signaling, although Ly6Chi monocytes required IFNAR for RIG-I expression. To probe functional responses in vivo, we intranasally administered a RIG-I-specific agonist, SLR14. Mapping RIG-I expression across the lung identified alveolar macrophages as a critical RIG-I sensor cell population, and depletion of alveolar macrophages, but not neutrophils, slightly impaired lung IFN responses. Together, these findings support the use of the RIG-ImScar model to probe RIG-I dynamics in vivo and predict functional sensor cell populations across tissues.

TGF-b/TIF1g signaling restrains CD8+ T cell expansion while preserving cytotoxic competence

Transforming growth factor b exerts complex and often opposing effects on CD8+ T cell biology, yet the molecular mechanisms that distinguish these functions remain poorly understood. Here, we identify TIF1g (TRIM33) as a critical signal threshold regulator that couples TGF b signaling to CD8+ T cell activation and cytotoxic function. In the presence of TGF b, TIF1g deficient CD8+ T cells bypass canonical suppressive signals and acquire a transcriptional program characterized by enhanced activation and proliferation. Despite this hyperactivated state, TIF1g deficient cells fail to acquire full effector function, exhibiting markedly reduced Granzyme B and Perforin expression under TGF b signaling. We confirmed this functional uncoupling in vivo using a secondary Listeria monocytogenes challenge model, in which TIF1g deficient CD8+ T cells underwent robust expansion yet failed to efficiently control bacterial infection because of impaired cytotoxic activity. In a lymphopenic homeostatic proliferation model, TIF1g deficiency disrupted cellular quiescence, leading to excessive proliferation and spontaneous effector differentiation. Consistent with these findings, loss of TIF1g accelerated B16 melanoma growth and was associated with reduced Perforin expression in tumor-infiltrating CD8+ T cells. Together, these findings identify TIF1g as a key regulator of TGF b mediated CD8+ T cell responses, uncoupling activation from cytotoxic differentiation and revealing a mechanism by which TGF b independently regulates proliferative and effector programs.

IL-4 Licenses B Cell Activation Through Cholesterol Synthesis

IL-4 is a pleiotropic cytokine that was first identified as a B cell co-mitogen over 30 years ago1. However, how IL-4 signaling mechanistically supports B cell proliferation is incompletely understood. Here, we find that the cholesterol biosynthetic program is transcriptionally upregulated by IL-4 signaling during the early B cell response to influenza virus infection and is required for B cell activation in vivo. Induction of lipid synthesis genes required both STAT6 and SREBP2 transcription factors, allowing IL-4 activated B cells to enter the cell cycle and proliferate in the absence of lipids. Genetic inhibition of de novo cholesterol synthesis via SREBP2 deletion reduced plasmablasts and subsequent germinal center B cell formation at steady state and following influenza infection. SREBP2-deficency blocked IL-4 mediated cell cycle entry, ER expansion, and subsequent proliferation in a cholesterol dependent manner. Further mechanistic studies revealed that ER cholesterol content promoted sustained STAT6 signaling associated with ER expansion and B cell survival. In sum, we demonstrate that the well-known ability of IL-4 to act as a B cell growth factor is through a previously unknown rewiring of specific lipid anabolic programs, relieving sensitivity of cells of environmental nutrient availability.

Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency

Humanized mouse study reveals CARD8-driven pyroptosis causes cytopenia in human HSPCs, indicating a species-specific mechanism and therapeutic target for DPP9 deficiency.

Borrelia Burgdorferi binds Serum Amyloid A and Modulates Subcutaneous Adipose Tissue Immune Signaling

Borrelia burgdorferi causes over 470,000 infections annually [1]. Following a tick bite, Borrelia spirochetes replicate in human skin and disseminate through tissues, including subcutaneous adipose tissue. Adipose tissue is a complex organ containing non-immune and immune cells that play a significant role in the immune response [2], yet little is known about adipose tissue signaling after Borrelia infection. We investigated the landscape of immune signaling within adipose tissue-resident cells during Borrelia infection in human tissue (skin and adipose tissue) ex vivo . Immune pathways overall were downregulated in adipose tissue during Borrelia infection. Despite this, adipose stem/progenitor cells exhibited increased pro-inflammatory and extracellular matrix (ECM)-related signaling (IL-6, MIF, collagen, laminin, fibronectin), positioning them as key hubs of intercellular communication during infection. Myeloid lineage cells showed cluster-specific upregulation of immune genes such as IL1B and TNF . Network analyses highlighted laminin, and strong outgoing MIF signals in all adipose-resident cell clusters. Among the identified genes modulated after Borrelia infection, we observed reduced expression levels of serum amyloid A in adipose tissue-resident cells, a marker typically elevated in Lyme disease patient serum during acute infection. Here, we show that human serum amyloid A1 and serum amyloid A2 directly bind B. burgdorferi spirochetes, using flow cytometry. Functionally, serum amyloid A2 reduces spirochete viability in vitro in a dose-dependent manner and enhances opsonization and phagocytosis by macrophages. Together, these findings show that adipose tissue is a site of active immune signaling in the setting of Borrelia infection and identifies SAA as a host defense factor against Borrelia .

IL-18 produced by pregnant uterus promotes essential inflammatory responses and fetoplacental growth

Placental insufficiency affects fetomaternal health throughout life. Although the interaction between the maternal uterine immune milieu and fetus-derived cells plays a crucial role in placental formation, several aspects remain unclear. Therefore, we conducted this study to investigate the effects of interleukin (IL)-18, a distinctive cytokine with both proinflammatory and anti-inflammatory properties, on the uterine immune milieu and placental development. Our results identified pregnant uterine smooth muscle cells as an important source of IL-18, which supports homeostatic type 1 immune responses. IL-18 facilitates appropriate placental development through uterine vascular remodeling and placental angiogenesis. Smooth muscle cell-specific Il18 knockout dam mice exhibited excessive cytotoxicity of uterine natural killer (NK) cells, impaired fetoplacental growth, and elevated maternal blood pressure, reflecting preeclampsia-like phenotypes. Their offspring demonstrated a tendency toward excessive weight gain and delayed neurodevelopment. Overall, this study emphasizes the essential role of IL-18 in placental formation and its wider implications for fetomaternal health.

FABP5 regulates ether lipid metabolism to ameliorate atopic dermatitis

Murine model shows FABP5 regulates platelet activating factor in skin inflammation, suggesting new therapeutic targets for atopic dermatitis.

Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors

Analysis shows chromatin accessibility impacts HSPC fate towards lymphoid or myeloid lineages, suggesting intervention points for altered hematopoiesis.

EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases

Chronic inflammatory skin diseases affect the health of millions of people worldwide, and those that feature fibrosis are refractory to treatments. The signals that determine whether fibrosis occurs during chronic skin inflammation are poorly understood. We generated a scRNA-seq atlas of seven inflammatory skin diseases and their healthy controls. Diseases with fibrosis demonstrate higher expression and activity of STAT1 in fibroblasts. Fibroblast STAT1 is required for skin fibrosis development in mice. STAT1 activation promotes a fibrotic gene expression profile which can be activated directly by EGFR in a JAK-independent manner and abrogated by genetic and pharmacologic STAT1 inhibition. The EGFR-STAT1 pathway is stimulated by high affinity EGFR ligands expressed by activated keratinocytes, suggesting keratinocyte-derived signals as triggers of skin fibrosis. In sum, fibroinflammatory skin diseases are characterized by fibroblast EGFR-STAT1 signaling that controls expression of fibrotic genes, elucidating an interferon independent function of STAT1 to mediate fibrotic skin diseases.

The cutaneous response to a mosquito bite is influenced by the diurnal rhythm

mosquitoes feed on mice throughout the day, and a bloodmeal is most often obtained at times of day that are equivalent to dawn (ZT1) and dusk (ZT11). We observed that cells in the murine skin elicited more differentially expressed genes at ZT11 compared to ZT1. Additionally, we detected more immune cells in the skin at ZT11 in response to a mosquito bite. These results suggest that assessments of host responses to a mosquito bite and mosquito-borne infections may be influenced by the diurnal rhythm.

Abstract PR-04: Targeting PRMT5 to modulate endogenous retroviruses expression in melanoma

This research demonstrates PRMT5 inhibition triggers type I interferon signaling in melanoma, suggesting potential synergy with immune checkpoint blockade.

Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody

Analysis reveals that EREG expression drives fibrosis in scleroderma and GvHD, suggesting therapeutic potential of EREG antibody.

Humanization of CD47 enables development of functional human neutrophils via postirradiation remodeling of the bone marrow

Humanized mouse model enhances myelopoiesis, resulting in functional human neutrophils and addressing immune response limitations.

2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer.

Updated guidelines provide comprehensive management strategies for differentiated thyroid cancer, suggesting best practices for treatment and monitoring outcomes.

Inflammatory cytokine interleukin-18 prevents murine miscarriage by inducing appropriate inflammation

This analysis demonstrates how interleukin-18 reduces miscarriage rates in pregnant mice, suggesting critical immune roles. Findings highlight inflammation's relationship with cytokines and miscarriage rates.

Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Large‐Scale Production of Transfusion‐Ready Red Blood Cells From Induced Pluripotent Stem Cells

Preclinical study demonstrates scalable production of functional red blood cells from human stem cells, indicating a viable pathway toward donor-independent bioreactor blood manufacturing.

Heterogeneity of IL-15-expressing mesenchymal stromal cells controls natural killer cell development and immune cell homeostasis

Bone marrow (BM) mesenchymal stromal cells (MSC) provide microenvironmental niches that support hematopoietic stem cells and regulate hematopoiesis. Whether functional heterogeneity among BM MSCs contributes to the development and survival of distinct immune cell lineages remains incompletely understood. Here, we use an Il15 knockin reporter and multiple conditional deletion mouse models to show distinct differences in IL-15 expression between BM MSC subtypes. Conditional deletion of Il15 in Osx + stromal cells results in decreased natural killer (NK) cell precursors, memory CD8 + T cells and NKT cells but not mature NK cells. Lepr + stromal cells support the survival of mature NK cells and memory CD8 + T cells in the BM of older mice, while endothelial cells support mature NK cells and memory CD8 + T cells in the blood but not in the BM. Thus, our data suggest that MSC subtypes differentially regulate the development and survival of IL-15-dependent immune cell lineages in the BM.

IL-18 produced by pregnant uterus promotes essential inflammatory responses and fetoplacental growth

Summary Placental insufficiency affects fetomaternal health throughout life. Although the interaction between the maternal uterine immune milieu and fetal-derived cells plays a crucial role in placental formation, several aspects remain unclear. Therefore, we conducted this study to investigate the effects of interleukin (IL)- 18, a unique cytokine with both proinflammatory and anti-inflammatory properties, on the uterine immune milieu and placental development. Our results identified pregnant uterine smooth muscle cells as an important source of IL-18, which supports homeostatic type 1 immune responses. IL-18 facilitates appropriate placental development through uterine vascular remodeling and placental angiogenesis. Smooth muscle cell–specific Il18 -knockout dam mice exhibited impaired fetoplacental growth and elevated maternal blood pressure, reflecting preeclampsia-like phenotypes. Their offspring demonstrated a tendency toward excessive weight gain and delayed neurodevelopment. Overall, this study emphasizes the essential role of IL-18 in placental formation and its wider implications for fetomaternal health. Graphical Abstract Highlights Smooth muscle cells in the pregnant uterine myometrium sufficiently produce IL-18 IL-18 induces type 1 immune responses in the uterine immune milieu IL-18 promotes maternal uterine vascular remodeling and placental angiogenesis IL-18-signaling deficiency in the mouse model shows the preeclampsia-like clinical course

Engineering Mice to Study Human Immunity

Humanized mice, which carry a human hematopoietic and immune system, have greatly advanced our understanding of human immune responses and immunological diseases. These mice are created via the transplantation of human hematopoietic stem and progenitor cells into immunocompromised murine hosts further engineered to support human hematopoiesis and immune cell growth. This article explores genetic modifications in mice that enhance xeno-tolerance, promote human hematopoiesis and immunity, and enable xenotransplantation of human tissues with resident immune cells. We also discuss genetic editing of the human immune system, provide examples of how humanized mice with humanized organs model diseases for mechanistic studies, and highlight the roles of these models in advancing knowledge of organ biology, immune responses to pathogens, and preclinical drugs tested for cancer treatment. The integration of multi-omics and state-of-the art approaches with humanized mouse models is crucial for bridging existing human data with causality and promises to significantly advance mechanistic studies.