Immunology & Cell Biology最新文献

T follicular regulatory (Tfr) cells have emerged as key mediators in controlling germinal center (GC) responses, preventing excessive immune activation and preserving self-tolerance. Initially thought to originate solely from thymic T regulatory cells (tTregs), recent findings reveal a more complex picture involving multiple differentiation pathways contributing to their heterogeneity. The natural route of differentiation comprises the most abundant subset, which originates from tTregs and retains the expression of CD25 (CD25⁺ nTfr), before transitioning into a more mature CD25-negative state within the GC (CD25⁻ nTfr). Conversely, the induced route (iTfr) includes Tfr cells that arise alongside nTfr cells but originate from peripheral Tregs or CD25-expressing Tfh cells, in addition to a late-GC subset (late Tfr) that emerges through the expression of FoxP3 by Tfh cells. The identification of circulating Tfr cells (cTfr) in peripheral blood, especially useful for studying immune dysregulation in humans, provides insights into their systemic roles and potential as biomarkers for immune dysfunction in different clinical scenarios. While it becomes evident that Tfr cells exhibit a heterogeneous nature, a deeper understanding of their distinct subsets could pave the way for targeted immunomodulatory strategies in the development of novel vaccines and therapeutics. This review provides a comprehensive overview of Tfr cell diversity, exploring their ontogeny, functional roles, and impact on immune homeostasis and disease.

Crohn's disease is a chronic, transmural inflammatory disease of the human gut. Changes in the fecal microbial composition and dysbiosis are consistent features in studies of Crohn's disease patients, but whether dysbiosis is a cause or consequence of inflammation remains unresolved. Genetic susceptibility plays a role in the development of Crohn's disease and has been linked to genes involved in recognition of intestinal bacteria by the mononuclear phagocyte system. The earliest visible lesions in Crohn's disease are aphthous ulcers, overlying Peyer's patches and lymphoid follicles. To identify mechanisms underlying the earliest stages of disease we compared gene expression in aphthous ulcers, Peyer's patches, inflamed and endoscopically normal mucosa from patients and controls using total RNA-seq. The resulting data were subjected to network analysis to identify coregulated gene expression signatures of cell types and processes. These results were compared to single-cell RNA-seq analysis of intestinal macrophages in normal and diseased mucosa. The analysis of aphthous ulcers revealed signatures of epithelial stress and antimicrobial defense, plasma cell activation and immunoglobulin production, monocyte recruitment, inflammatory gene expression and induction of interferon-γ. These signatures were not present in the normal appearing mucosa adjacent to aphthous ulcers, which were similar to healthy control mucosa. Given the role of Peyer's patches and lymphoid follicles in sampling the luminal contents, these findings suggest the initial lesion in Crohn's disease arises from the uptake of bacteria and the activation of multiple host defense pathways rather than the breakdown of epithelial barrier integrity and widespread bacterial translocation.

Macrophages are a key cell type of the innate immune system and are involved at all steps of inflammation: (i) they present antigens to initiate inflammation, (ii) they clear up foreign bodies through phagocytosis and (iii) they resolve inflammation by removing or deactivating mediator cells. Many subtypes of macrophages have been identified, classified by their niche and/or embryonic origin. In order to better develop therapies for conditions with macrophage dysfunction, it is crucial to decipher potential sex differences in key physiological mediators of inflammation so that treatment efficacy can be ensured regardless of biological sex. Here, we conduct a meta-analysis approach of transcriptomics data sets for male vs. female mouse macrophages across 8 niches to characterize conserved sex-dimorphic pathways in macrophages across origins and niches. For this purpose, we leveraged new and publicly available RNA-sequencing data sets from murine macrophages, preprocessed these datasets and filtered them based on objective QC criteria, and performed differential gene expression analysis using sex as the covariate of interest. Differentially expressed (DE) genes were compared across data sets and macrophage subsets, and functional enrichment analysis was performed to identify sex-specific functional differences. Consistent with their presence on the sex chromosomes, three genes were found differentially expressed across datasets (i.e. Xist, Eif2s3y and Ddx3y). More broadly, we found that female-biased pathways across niches are more consistent than male-biased pathways, specifically relating to the extracellular matrix. Our findings increase our understanding of transcriptional similarities across macrophage niches and underscore the importance of including sex as a biological variable in immune-related studies.

The field of immunology in Chile has evolved remarkably over the past few decades, from a nascent discipline to a dynamic and rapidly developing community with significant international visibility. In this commentary, we, Fabiola Osorio and María Rosa Bono, offer personal reflections on the challenges and opportunities facing Chile's immunology community. As researchers who both returned to Chile after extensive training abroad, we have seen the dynamic nature of the Immunology field within our country. Our opinions also arise from our experiences as past presidents of the Chilean Association of Immunology (ASOCHIN; 2016–2019 MRB; 2019–2021 FO), the main scientific society congregating immunology researchers in Chile, where we have witnessed firsthand the growth of the local immunological community. Our testimonies and those of our colleagues highlight the resilience, creativity and collaborative spirit that have allowed Chile to carve out its place in global immunology.

In this article for the Highlights of 2024 Series, we discuss recent discoveries in Treg immunometabolism, which reveal how inflammatory niches alter Treg fate and function through distinct metabolic cues. Key findings include IL-21-driven mitochondrial dysfunction, lactate-enhanced OXPHOS via MGAT1, sphingolipid-dependent Treg differentiation in tumors, ferroptosis susceptibility under high-fat diets, and sex-specific adipose Treg subsets modulating glucose homeostasis. Together, these insights highlight potential metabolic targets to restore Treg function in inflammatory diseases and cancer.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU), significantly impacts quality of life. Despite significant advances in the management of the conditions, responses to treatments vary greatly, and this is due partly to our natural genetic variation. Here we will review the evidence for whether single nucleotide polymorphisms (SNPs) have the potential to guide treatment decisions for people with IBD. We will first consider SNPs that exhibit strong associations with IBD pathogenesis and their relevance to epithelial barrier integrity, cytokine production, and immune system function. Then, we will cover those SNPs implicated in altering response to our various current IBD therapeutics, including the recently implemented drugs ustekinumab and tofacitinib. Finally, we will explore lesser-known SNPs that exhibit complex relationships with the disease and which may be undervalued as pharmacogenetic tools. Overall, it will be demonstrated that SNPs associated with IBD pathology are largely distinct from those predicting response to treatments and that new discoveries of clinically useful tools can be expected from therapy-focused investigations. Given the growing list of treatments available, we argue that beneficial personalization of treatments based on SNPs is still underutilized.

In this article for the “Highlights of 2024” Series, we discuss findings by our group and others that the Alzheimer's disease (AD) risk genetic variant apolipoprotein E ε4 (APOE4) is associated with peripheral immune dysregulation and chronic inflammation. We hypothesize that this leads to AD development via proinflammatory immune cells attacking the blood–brain barrier (BBB) to weaken it. Immune cells then infiltrate into the brain where they interact with brain cells to drive neuroinflammation, neurodegeneration, and AD pathology.

In this Research Highlight, we explore 5 influential basic and translational articles published in 2024 that shed light on the biology of age-associated B cells (ABCs) and their emerging role in autoimmunity.

The path to becoming an academic researcher is winding. The trajectories and landscapes of academic success may mean many different things to each of us. There is no clear or direct path anymore. Here, I share with you my journey, giving important insights I have gathered over the years, defining what parts of this career make it worthwhile.

Collectively, 2024 has significantly increased the wealth of knowledge regarding antibody-secreting cell heterogeneity in health and disease. This ‘Highlights of 2024’ article discusses key studies contributing to the understanding of how tissue residency and disease state influence the transcriptional programming of antibody-secreting cell phenotypes.