Immunology & Cell Biology最新文献

Route-dependent effects of GM-CSF on systemic and mucosal myeloid activation in rhesus macaques. Subcutaneous GM-CSF administration induced rapid systemic expansion of myeloid cells, accompanied by chemokine release (MCP-1, CXCL13 and IL-1RA) and enrichment of Fc receptor-bearing myeloid populations (CD64⁺ and CD32⁺) in circulation. These cells subsequently migrated to rectal and vaginal mucosa along chemokine gradients, resulting in sustained mucosal infiltration without overt systemic inflammation. In contrast, topical mucosal GM-CSF delivery elicited no detectable systemic expansion, chemokine induction or myeloid recruitment. Figure made in ©BioRender—biorender.com.

Tumor-associated macrophages (TAMs) play critical roles in the progression of triple-negative breast cancer (TNBC), yet the mechanisms underlying their differentiation remain unclear. Heterogeneity of macrophages in TNBC tissues was comprehensively dissected using single-cell transcriptome analysis. The crucial role of Apolipoprotein C1 (APOC1) in macrophages was investigated through loss or gain-of-function experiments. Single-cell analysis revealed that myeloid cells were the second most metabolically active cell type in TNBC after epithelial cells, with a subset of lipid-associated macrophages (LA-TAMs) potentially linked to TNBC progression. Further analysis showed significant upregulation of APOC1 in myeloid cells and LA-TAMs, with pseudo-temporal expression profiling indicating that APOC1 tended to be expressed in the mid-late stages of macrophage development. KEGG analysis highlighted significant enrichment of APOC1 in glycolysis-related pathways. Cell experiments in vitro demonstrated that macrophages overexpressing APOC1 exhibited enhanced glycolytic activity, a skew toward an immunosuppressive M2 phenotype, and increased secretion of anti-inflammatory cytokines. APOC1-deficient macrophages effectively slowed the progression of TNBC by suppressing the proliferation, migration, and invasion of TNBC cells. These findings suggested that APOC1 promoted macrophage polarization toward the pro-tumor M2 phenotype by activating the glycolytic pathway, thereby facilitating the malignant progression of TNBC. This study provides new insights into the role of macrophages in TNBC and establishes a theoretical basis for developing immunotherapeutic strategies targeting APOC1.

Cigarette smoke is a leading cause of lung cancer, promoting disease progression through remodeling of the immune microenvironment. This study explores the impact of cigarette smoke exposure on the m⁶A reader YTHDC2, its role in inducing macrophage senescence, and the consequent formation of a tumor-supportive inflammatory niche in lung cancer. Single-cell RNA sequencing of lung cancer tissues revealed an enrichment of senescent macrophages with decreased YTHDC2 expression in smokers compared to non-smokers. In vitro experiments showed that cigarette smoke extract (CSE) suppressed YTHDC2 expression in macrophages, resulting in enhanced cellular senescence, increased secretion of pro-inflammatory cytokines and M2-like polarization. Overexpression of YTHDC2 attenuated macrophage senescence by regulating RPS8, thereby limiting the formation of a tumor-promoting microenvironment. In vivo studies using a cigarette smoke-exposed lung cancer model confirmed the role of YTHDC2 in smoke-induced immune microenvironment modulation and tumor progression. These findings identify YTHDC2 as a critical regulator of smoke-induced macrophage senescence and the tumor-promoting microenvironment, providing a potential therapeutic target for lung cancer in smokers.

Silicosis is a progressive occupational lung disease marked by persistent silica-induced inflammation and irreversible pulmonary fibrosis. The NLRP3 inflammasome, an innate immune sensor, has been implicated as a key driver of silica-triggered inflammation and fibrosis in preclinical models. However, the specific role of NLRP3 in immune cells, particularly within myeloid cells (monocytes, macrophages and neutrophils), remains poorly defined. In this study, we investigated the in vivo contribution of myeloid-derived NLRP3 to silica-induced lung pathology using a conditional NLRP3 knockout mouse model (LysM^Cre Nlrp3^fl/fl). These mice exhibited efficient deletion of NLRP3 in both resident and infiltrating lung myeloid cells. Following intranasal delivery of 2 mg of silica, NLRP3 expression was upregulated in myeloid cells by day 3. Despite upregulation of NLRP3 in myeloid cells by day 3, early inflammasome activation in the tissue and BAL, including caspase-1 cleavage and IL-1β and IL-18 secretion, remained intact. During the chronic phase (days 14 and 28), myeloid NLRP3 deletion did not mitigate hallmark features of silicosis, including alveolitis, structural lung damage, airway remodeling or peribronchial alpha-smooth muscle actin expression. Furthermore, the formation and size of silicotic nodules were unaffected. These findings indicate that NLRP3 expression in myeloid cells is not essential for the development of silica-induced pulmonary inflammation, tissue damage or fibrosis. This work highlights the need to explore alternative cellular sources and mechanisms of NLRP3-driven pathology in silicosis.

Naive CD4⁺ T cells are highly plastic cells that can differentiate into various T helper (Th) cell subsets upon activation. It is well accepted that the vital expression of specific transcription factors and effector cytokines that characterize the different Th cell fates can be stabilized by epigenetic mechanisms including DNA methylation. However, a global view on DNA methylation profiles in Th cell subsets is currently lacking. In this study, we identified the DNA methylomes of human naive T cells, Th1, nonclassic Th1, and Th17 cells by performing a whole-genome bisulfite sequencing analysis. Differentially methylated regions (DMRs) obtained by pairwise comparison of the Th cell methylomes indicate a close relationship between ncTh1 and Th17 cells on a genome-wide level. However, similar methylation patterns at key gene loci such as TBX21, IFNG, SLAMF7, and SLAMF8 may explain the functional proximity of ncTh1 to Th1 cells. Using luciferase reporter assays, we demonstrated that DNA methylation can modulate the transcriptional activity of promoter-located DMRs belonging to genes such as GSPT1, SRSF7, SLAMF7, SLAMF8, TIGIT, and PDCD1. Upon stimulation, SLAMF7 gene expression was upregulated exclusively in IFN-γ producing cells, with SLAMF7⁺ cells appearing among both Th1 and ncTh1 cells. Taken together, the DNA methylomes of proinflammatory human Th cells provide useful data for better functional characterization of the lineages and identification of key genes for therapeutic intervention.

LAG3-MHC-II binding recruits LAG3 to the immune synapse, suppressing T-cell activation through induced formation of condensates between the LAG3 intracellular domain and that of the CD3ε subunit. The BiTS molecule designed by Du et al. mimics the effect of MHC-II binding by tethering LAG3 to the TCR.

The role of CD8⁺ T cells, as cytotoxic cells, being critical against intracellular pathogens is well known. Through the killing of infected (target) cells, CD8⁺ T cells impair intracellular pathogens' replication. However, extracellular pathogens are not directly targeted by CD8⁺ T cells, since these pathogens do not express MHC-I-peptides, responsible for the activation of the cytotoxic activity of CD8⁺ T cells. In this sense, how CD8⁺ T cells affect the course of extracellular infections is discussed in this review, underscoring the important regulatory functions of CD8⁺ T cells, killing phagocytes and other cells that are able to cross-present extracellular antigens. In addition, the role of CD8⁺ T cells in the modulation of immune responses through the secretion of cytokines, such as gamma interferon (IFNγ), is also discussed in the context of extracellular infections.

Myeloid cells play critical roles as Fc effector cells in antibody-mediated immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that promotes the recruitment and activation of multiple myeloid populations and has been used in combination with vaccines/treatments against infectious diseases, inflammatory conditions and cancers. To evaluate GM-CSF-mediated kinetics of immune cell expansion and immune outcomes, we compared subcutaneous (subQ) and topical hypoosmolar (intravaginal/intrarectal) administration in vivo using rhesus macaques (RM), as they provide easy access to longitudinal mucosal tissue sampling and are a critical model species for vaccines/therapeutics development. While topical GM-CSF did not result in a major change, neutrophils, eosinophils and monocytes were elevated within 1–3 days of subQ GM-CSF administration, with peak eosinophil and neutrophil enrichment in blood at days 7 and 8, respectively. Corresponding elevations of neutrophils, eosinophils, total CD64⁺ and total CD32⁺ were observed at days 7 and 14 in rectal biopsies, indicating general Fc effector cell accumulation in these animals. Histological evaluations of vaginal biopsies showed myeloid cell infiltration at day 14 of subQ GM-CSF treatment. Further, subQ GM-CSF administration resulted in myeloid cell activation and trafficking, as evidenced by elevated levels of cytokines (CXCL13, MCP-1, IL-1RA). Importantly, neither subQ nor topical GM-CSF administration induced overt systemic inflammation or adverse clinical impacts. Overall, our findings delineate the kinetics of systemic and mucosal myeloid cell expansion, activation and trafficking achieved by subQ GM-CSF administration in RM. These findings will inform the use of GM-CSF as an adjuvant in clinical applications where myeloid cell mobilization is advantageous.

Sayan Ghosh¹, Sreetama Choudhury¹, Sudeshna Mukherjee¹, Payal Gupta¹, Olivia Chowdhury¹, Rathindranath Baral² & Sreya Chattopadhyay^1,3

1 Department of Physiology, University of Calcutta, UCSTA, Kolkata, India

2 Chittaranjan National Cancer Institute, Kolkata, India

3 Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India

Immunology & Cell Biology 2019; 97: 470–484. https://doi.org/10.1111/imcb.12227

Correction to: Immunology & Cell Biology 2025; https://doi.org/10.1111/imcb.70056

The immunohistochemistry data of thymic tissue from mice in the LPS group panels of Figure 2b and Figure 5b had similar/overlapping architecture, which is not correct and can be noted as a human error. The authors have now added new LPS panels (replicates from same experiment) for Figure 2b and Figure 5b for the readers. The authors confirm that all the experimental results and corresponding conclusions mentioned in the paper remain unaffected. The corrected LPS panels of Figure 2b and Figure 5b are shown as follows:

The authors apologize for this error.