Journal of Leukocyte Biology最新文献

Regulatory T cells (Tregs) play a crucial role in the immune system, and their dysfunction can lead to the development of autoimmune conditions. In cancer, tumors frequently hijack the immunosuppressive function of Tregs to evade immune responses. Due to their central role in key pathological processes, Tregs have gained increasing attention as promising targets for various clinical applications. However, their relative scarcity (∼5% to 10% of CD4+ T cells) and instability presents a technical challenge for research and therapeutic development. In congenic animal models used to investigate autologous cell transfer-based therapies, this challenge is even greater, as Treg donor animals may only be able to provide cells to a small number of recipient mice. Here, we present an optimized protocol for ex vivo editing and expansion of mouse Tregs. Because a recent study demonstrated the anticancer potential of SRC-3 KO mouse Tregs, we use them here as a case study.

Following the 2025 Nobel Prize in Physiology or Medicine for the discovery of regulatory T cells (Tregs), a recent article in Nature Communications reports the generation of allogeneic, genome-edited Tregs engineered to evade immune rejection while retaining suppressive function. Through non-viral CRISPR deletion of B2M and CIITA and insertion of an HLA-E-B2M fusion, the authors produced hypo-immunogenic Tregs that persisted and promoted graft tolerance in humanized mice. In this News and Views, the promise and challenges of such universal "off-the-shelf" Tregs are discussed, emphasizing how genome engineering is reshaping Treg biology into a new era of programmable immune tolerance.

Neuroinflammation plays a vital role in determining the trajectory of Alzheimer's disease (AD) progression. In the AD brain, microglial exposure to pathological amyloid β (Aβ42) and tau peptide aggregates results in an NLRP3 inflammasome-activated proinflammatory response that ranges from mild to severe. Recently we have shown that dementia subjects with higher levels of soluble TAM receptors Tyro3 and AXL in the cerebrospinal fluid indicated cognitive protection. The molecular mechanism for this protective effect of TAM receptors is unknown. Here, we identified a beneficial role of TAM receptors using Tyro3-overexpressing (Tyro3OE) and Axl-overexpressing THP-1 cells. In the Tyro3OE cells, the levels of the proinflammatory cytokine IL-1β were markedly decreased in the AD microenvironment (tau + Aβ42) and the classical NLRP3 inflammasome model (lipopolysaccharide [LPS] + nigericin) in comparison with the control cells. This was mediated by increased STAT1 phosphorylation and reduced IL-1β transcription enhancer C-EBP-β in Tyro3OE cells. The use of the JAK1/2 inhibitor ruxolitinib reduced the phosphorylation of STAT1, leading to a partial restoration of IL-1β in the Tyro3OE cells. Last, we found a significantly reduced IL-1β in the brains of AD mice that has activated TAM signaling through Gas6-α-Aβ lentiviral injection. In summary, TAM receptor Tyro3 overexpression decreased AD-associated IL-1β release from macrophages thereby uncovering a potential beneficial role for TAM receptors during neuroinflammation in AD.

Macrophage migration inhibitory factor (MIF) is broadly produced by various cell types, particularly immune cells, and functions as a key modulator of innate and adaptive immunity. Increasing evidence has linked MIF to the pathogenesis of both solid tumors and hematologic malignancies, including chronic lymphocytic leukemia (CLL). We previously showed that the global deletion of Mif in the TCL1 transgenic mouse model for CLL significantly delayed disease development leading to longer overall survival of the knockout mice. In this study, we demonstrated that adaptive transfer of murine CLL cells failed to establish disease in Mif-deficient recipients due to impaired homing of leukemic cells into the spleens, indicating that host-derived Mif is essential for leukemic infiltration and expansion. To identify the most relevant source of Mif in CLL, we generated two CLL mouse strains with B-lymphoid- or myeloid-lineage-specific Mif deletion. In contrast to the global Mif knockout, neither conditional Mif knockout significantly altered CLL progression, illustrating that the cellular source of Mif is less critical than its systemic presence in the tissue environment.

Neutrophils, our frontline of defense against pathogens, exhibit pronounced sexual dimorphism in ontogeny, phenotype, and effector functions. Throughout the human lifespan, estrogen and androgen signaling, together with sex-linked genetic regulators, orchestrate neutrophil production, maturation, and immune activity, contributing to immunological differences between sexes observed across lifespan. Differences in neutrophil antimicrobial and immune responses contribute to disease susceptibility, with females having not only stronger antimicrobial defenses, but also a higher risk of autoimmunity, while males experience greater severity of infections and different cancer risks. This review summarizes and discusses the existing evidence on regulation of neutrophil biology by sex. We (1) describe the dynamics of neutrophils throughout human life in both females and males, (2) delineate sex-specific regulation of neutrophil phenotype and function, and (3) examine the significance of these differences in the susceptibility and outcomes of neutrophil-driven diseases.

Rhesus theta defensin (RTD)-1, a cyclic antimicrobial peptide, regulates gene expression and immune signaling pathways in cell culture and animal models of immune-mediated diseases. In lipopolysaccharide-stimulated cells, RTD-1 inhibition of proinflammatory cytokine secretion and gene expression is mediated through inhibition of the NF-κB and MAP kinase signaling pathways. To gain insights into RTD-1 regulation of naïve cells, we performed RNA sequencing (RNA-seq) to determine the effect of the peptide on global gene expression in human monocytes and THP-1 monocytes. In both cell types, analysis of differentially expressed genes revealed stimulation of interferon and antiviral gene expression pathways. RTD-1 induced Y701 phosphorylation of STAT1 and activated the ISRE reporter in a JAK-dependent manner. Stimulation of the ISRE reporter by RTD-1 was interferon-α/β receptor dependent but was independent of its NF-κB inhibitory activity in lipopolysaccharide-stimulated cells. RTD-1 inhibited infection of vesicular stomatitis virus pseudotyped with G glycoprotein or SARS-CoV-2 spike protein in THP-1 and Vero E6 cells, respectively. RTD-1 also inhibited infection of Calu-3 2B4 cells by SARS-CoV-2 virus, demonstrating antiviral activity of RTD-1 in diverse cell types. These results demonstrate that RTD-1 stimulates interferon and antiviral pathways, potentially priming cells for resistance to viral infection.

Eosinophils play an important role in mediating itch and inflammation in dermatitis. The role of the eosinophil granule protein eosinophil peroxidase (EPX) in mediating inflammation and itch was tested in a dermatitis mouse model. Mice were sensitized to trimellitic anhydride (TMA) and subsequently challenged chronically on the ear to establish dermatitis. Loss of EPX (in EPX (-/-) mice) or blocking EPX with the drug resorcinol significantly reduced dermatitis in mice exposed to TMA. Resorcinol also reduced levels of thymic stromal lymphopoietin protein (TSLP) in skin. Further studies showed that EPX increased different cytokines in keratinocytes in cell culture via two distinct mechanisms. EPX induced TSLP expression requires lysophosphatidic acid signaling while EPX induced expression of TNF-a, CSF2, CSF3, and IL1a required IL-1 signaling. We also showed that blocking IL-1 reduced inflammation in skin following TMA exposure in mice. Thus, EPX is an important mediator of inflammation and itch, that are mediated via at least two pathways. This suggests that both EPX and its signaling pathways may provide novel therapeutic strategies in dermatitis.

Myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes, constitute a versatile arm of the immune system, serving as frontline sentinels that detect and react to environmental cues and orchestrate tailored immune responses. Their ability to respond promptly to distinct threats depends on dynamic processes that include differentiation, antigen presentation, and secretion of pro-inflammatory and antimicrobial mediators. These functions are tightly linked to the integrity of the endoplasmic reticulum (ER), an essential organelle responsible for synthesis, folding, and modification of proteins. Disruption of ER homeostasis is commonly induced by infection, inflammation, autoimmunity, or cancer settings, leading to ER stress and activation of the unfolded protein response (UPR), a 3-pronged signaling pathway aiming to restore the fidelity of the cellular proteome. Among UPR branches, the inositol-requiring enzyme 1 (IRE1)/XBP1 pathway has emerged as a central regulator of myeloid cell function, integrating proteostatic stress with immune modulation. Despite growing evidence positioning the IRE1/XBP1s axis as a pivotal immunological target bearing biomedical potential, the context-dependent outcomes of this UPR branch in myeloid cells, ranging from protective to maladaptive, remain incompletely understood. In this review, we explore the multifaceted roles of IRE1 in shaping myeloid cell responses across physiological and pathological states, highlighting molecular mechanisms and their impact on immune homeostasis and disease pathogenesis.

The cytokine CSF-1 and its tyrosine kinase-encoding receptor CSF1R are important for the development and proliferation/survival of most tissue macrophages. We recently identified TNF-α-induced protein 2 (TNFAIP2) as a unique cellular regulator of CSF1R activation: TNFAIP2 increased the response of macrophages to CSF-1, which might be explained at least in part by the induction of CSF1R clustering by TNFAIP2, since CSF1R clusters accelerate CSF-1-induced CSF1R dimerization/activation. Here, we report an enhanced trafficking of CSF1R to the cell surface as an additional mechanism by which TNFAIP2 increases macrophage response to CSF-1. The mutation in the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding site of TNFAIP2 or CSF1R, or the deprivation of cellular PIP2 reduced the enhanced CSF1R trafficking by TNFAIP2, indicating the importance of PIP2-mediated membrane localization of TNFAIP2 and CSF1R. Mechanistically, a small GTPase RalA and the exocyst complex involved in vesicle trafficking were required for the enhanced CSF1R trafficking by TNFAIP2. Interestingly, the RalA-exocyst complex cascade was also required for the enhanced CSF1R clustering by TNFAIP2. Our results suggest that TNFAIP2 enhances intracellular trafficking and cluster formation of CSF1R through PIP2, RalA, and the exocyst complex, thereby increasing the macrophage response to CSF-1. Our results also suggest that TNFAIP2 regulates other receptor tyrosine kinases.

Adoptive cell therapy using ex vivo expanded autologous Tregs could be a novel therapeutic approach for cell-based immunotherapy in dogs. This study aimed to expand dog Treg lymphocytes via the use of tregitopes. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy beagle dogs and stimulated with peptides: human tregitope EEQ; two potential canine tregitopes, EQF and PSV; and whole canine IgG in primary cultures. In addition, lymphocytes were simultaneously stimulated with peptides and canine vaccine antigens. The frequencies of Treg lymphocytes (CD4 + CD25 + Foxp3+, CD4 + Foxp3+) and activated lymphocytes (CD4 + CD25+) were determined by flow cytometry. A statistically significant increase in the frequency of CD4 + Foxp3+ and CD4 + CD25 + Foxp3+ lymphocytes stimulated with PSV and EQF peptides and canine IgG was observed. No increase in the Treg lymphocyte frequency occurred after EEQ Tregitope stimulation or vaccine antigen costimulation. Canine Treg lymphocytes isolated from peripheral blood are sensitive to stimulation with peptides with potential tregitope properties derived from canine proteins.