Immunology & Cell Biology最新文献

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.

Optic neuritis (ON), characterized by inflammation and demyelination of the optic nerve, is a leading cause of vision impairment. It frequently manifests as the initial symptom and a recurrent syndrome in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). While the diagnosis of ON is relatively straightforward, predicting relapses and managing the disease remain significant challenges. The myelination of retinal ganglion cell axons is essential for the efficient and accurate transmission of signals between optic neurons. Oligodendrocytes, specialized glial cells responsible for myelination, engage in metabolic interactions with neurons. Demyelination and inflammation of the optic nerve locally release a variety of metabolites and inflammatory factors within this unique anatomical region. Cerebrospinal fluid (CSF), in close proximity to ON lesions, is a critical source for identifying metabolic and inflammatory biomarkers that are essential for tracking disease activity and guiding therapeutic decisions. This comprehensive review examines the structure, myelination and demyelination of the optic nerve, as well as the immunopathological mechanisms underlying ON. It also explores changes in CSF constituents, including pleocytosis, antibodies, cytokines, proteins, metabolites and extracellular vesicles. Special emphasis is placed on elucidating the pathological contributions of metabolites in MOGAD, MS and NMOSD. By advancing our understanding of these mechanisms, this review elucidates the potential predictive roles of CSF constituents in acute attacks and relapses of optic neuritis.

Vγ9/Vδ2 T cells represent the largest γδ T-cell population in human blood and possess a unique responsiveness towards microbial organisms by sensing the metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) in the context of the butyrophilin family members BTN2A1 and BTN3A1. Curiously, the bacterium Staphylococcus aureus does not produce HMB-PP but appears to be capable of inducing activation, cytokine expression and proliferation of Vγ9/Vδ2 T cells regardless, through a largely unknown mechanism. We here provide a comprehensive review of the existing literature around Vγ9/Vδ2 T-cell responses to S. aureus and discuss potential pathways, ligands and biological functions.

Activated PI3K delta syndrome 1 (APDS1) is caused by a heterozygous germline gain-of-function (GOF) variant in PIK3CD, which encodes the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K). APDS1 patients display a broad range of clinical manifestations and perturbations in cellular phenotype. One of the most striking features is the dysregulation of the T-cell compartment, characterized by an increase in memory T cells, including Tfh cells, and a concomitant decrease in naïve T cells. We have previously shown that many of these changes in T-cell populations were T-cell extrinsic and were also induced in WT T cells that developed in the presence of PI3K GOF cells. Here we dissected the drivers of dysregulated T-cell activation using a mouse model of APDS1. This revealed that PI3K GOF macrophages and DCs made little contribution to the aberrant T-cell activation. Instead, PI3K GOF T cells were able to drive the loss of WT naïve CD4⁺ T cells, while dysregulated PI3K GOF B cells mediated an increase in Tfh cells. Surprisingly, despite previous reports of increased PI3K signalling driving dysregulated inflammatory Tregs, we saw no evidence for Pik3cd GOF Tregs acquiring an inflammatory phenotype and driving T-cell activation. These studies provide new insights into the role of PI3K in immune cells and how increased PI3K can drive T- and B-cell dysregulation and contribute to the phenotype of APDS1 patients.

Early career researchers (ECRs) are often faced with uncertainty about their professional futures, a challenge exacerbated by the increasing pressures within the academic research landscape. As ECRs navigate their next steps in science, mentorship is crucial, particularly as they face points of decision-making and possible career diversions from the traditional postdoctoral-to-professor pathway. In response to these challenges, the second iteration of the Australian and New Zealand Society of Immunology (ASI) Mentor-Mentee Program aimed to provide mentorship and training to ECRs about academic career pathways in research and education to bridge the professional communities, values and advice of these two often independent career choices. As a component of the program, three eminent Australian immunologists in research-intensive, teaching and research (TnR) and education-focused careers shared their professional journeys and experiences which led to their chosen career pathways in national workshops. Here, we share their insights, lessons learned and professional development tips to establish an academic career. By outlining the three primary scientific academic career pathways available post-PhD, we aim to inform and inspire the next generation of immunologists as they consider the diversity of possible academic careers ahead.