Immunology & Cell Biology最新文献

This report presents findings from a group of UK-based researchers with expertise in the use of animal models for bone marrow ablation and reconstitution. The primary aim is to facilitate the implementation of the Three Rs (Replacement, Reduction and Refinement), with an emphasis on refinement. Bone marrow ablation and reconstitution procedures are performed for a number of different purposes and conducted predominantly in mice. These procedures can induce significant suffering, classified as "severe", Category E or Category D/E under European, US and Canadian legislation, respectively. Although severity categorization is not mandated in countries such as Australia and New Zealand, legislation still requires that the level of animal suffering must be minimized to the greatest extent possible. This report identifies specific animal welfare issues and proposes practical measures aimed at reducing both animal use and suffering.

Pursuing an international scientific career is a fantastic opportunity for personal and professional growth, but it also poses unique challenges, which can be particularly daunting for researchers coming from resource-limited countries. Drawing from personal experience, this article provides insights into navigating the transition to working abroad in academia and developing a sustainable career while integrating into a new culture. From predeparture preparations to achieving career independence, I discuss practical aspects of crafting tailored applications to contact potential advisers, contemplating visa-related challenges, establishing collaborations and emphasizing the value of finding appropriate mentorship to help you adapt to new cultural and professional environments. The article also underscores the importance of resilience, adaptability and redefining career success as a dynamic, nonlinear process. I present an original perspective on career planning, inspired by maritime voyage planning, to address the complexities of balancing personal and professional life, particularly during transitional periods. This approach, which combines four key stages of planning, namely, appraisal, planning, execution and monitoring, serves as a model for early-career researchers to navigate the unpredictable tides of academic work and personal life abroad with the goal of sustaining progress and well-being. These reflections aim to empower scientists preparing for or adapting to international research environments, fostering resilience and adaptability for long-term success abroad.

Understanding antigen-specific T-cell responses is crucial for advancing immunotherapies and vaccine development. This study proposes a novel approach combining two complementary assays: the 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay (tracking proliferation over 0–48 h) and the VPD450 dye dilution assay (tracking proliferation over 4–6 days). Integrating these techniques provides additional insights into T-cell proliferation kinetics. Both assays were independently optimized using anti-CD3 and anti-CD28 polyclonal T cell stimulation. 1 μM VPD450 is suitable for assessing T-cell proliferation. The EdU concentration should match the stimulation strength, requiring higher concentrations to efficiently track DNA replication detection during increased cellular division. Day 5 was the optimal read-out day for the EdU incorporation assay. We then combined the VPD450 dye dilution and EdU incorporation assays. As a proof of principle, we stimulated PBMCs from healthy donors with tetanus toxoid to assess antigen-specific T-cell responses. Additionally, we demonstrated the assay's application in drug research by evaluating proliferation in a mixed lymphocyte reaction with abatacept, an agonistic anti-CTLA-4 antibody. This combined approach offers qualitative insights into T-cell proliferation kinetics, beneficial for assessing novel vaccine efficiency or for designing new treatments targeting T cell proliferation, such as in autoimmune settings.

Neurodegeneration and neuroinflammation disorders are mainly the result of the deposition of various proteins, such as α-synuclein, amyloid-β and prions, which lead to the initiation and activation of inflammatory responses. Different chemokines are involved in the infiltration and movement of inflammatory leukocytes into the central nervous system (CNS) that express chemokine receptors. Dysregulation of several members of chemokines has been shown in the CNS, cerebrospinal fluid and peripheral blood of patients who have neurodegenerative disorders. Upon infiltration of various cells, they produce many inflammatory mediators such as cytokines. Besides them, some CNS-resident cells, such as neurons and astrocytes, are also involved in the pathogenesis of neurodegeneration by producing chemokines. In this review, we summarize the role of chemokines and their related receptors in the pathogenesis of neurodegeneration and neuroinflammation disorders, including multiple sclerosis, Parkinson's disease and Alzheimer's disease. Therapeutic strategies targeting chemokines or their related receptors are also discussed in this article.

A recent article has shown that blocking NKp46 signaling reduces injury, highlighting these cells as key drivers of organ damage and potential therapeutic targets in autoimmune diseases. In lupus nephritis, NKp46⁺ ILC1s orchestrate kidney inflammation by producing CSF2, driving the expansion of pro-inflammatory macrophages that infiltrate epithelial niches and exacerbate tissue damage.

The α_Lβ₂ integrin LFA-1 plays a key role in T-cell adhesion to the endothelial vasculature and migration into both secondary lymphoid organs and peripheral tissues via interactions with its target protein ICAM-1, but the pathways that regulate LFA-1-mediated T-cell polarity and migration are not fully understood. In this study we screened two RNAi libraries targeting G protein-coupled receptors (GPCR)/GPCR-associated proteins and kinases in a HuT 78 T cell line model of LFA-1-stimulated T-cell migration. Based on staining of the actin cytoskeleton, multiple parameters to measure cell morphology were used to assess the contribution of 1109 genes to LFA-1-mediated T-cell polarity and migration. These RNAi screens identified a number of both novel and previously identified genes that either increased or decreased the polarity and migratory capacity of these cells. Following multiparametric analysis, hierarchical clustering and pathway analysis, three of these genes were characterized in further detail using primary human T cells, revealing novel roles for the heterotrimeric G protein subunit Gβ1 and Casein Kinase 2 in LFA-1-mediated T-cell polarity and migration in vitro. Our studies also highlighted a new role for ICAP-1, an adaptor protein previously described to be associated with β1 integrins, in β2 integrin LFA-1-directed migration in T cells. Knockdown of ICAP-1 expression in primary T cells revealed a role in cell polarity, cell velocity and transmigration towards SDF-1 for this adaptor protein. This study therefore uncovers new roles for GPCR/GPCR-associated proteins and kinases in T-cell migration and provides potential novel targets for modulation of the T-cell immune response.

T cells of the adaptive immune system recognize pathogens and malignantly transformed cells through a process called antigen presentation. During this process, peptides are displayed on major histocompatibility complex (MHC) class I and II molecules. Self-reactive T cells are typically removed or suppressed during T-cell development and through peripheral tolerance mechanisms, ensuring that only T cells recognizing peptides that are either absent or present in low abundance under normal conditions remain. This selective process allows T cells to respond to peptides derived from foreign proteins while ignoring those from self-proteins. However, T cells can also respond to peptides derived from proteins that have undergone post-translational modifications (PTMs). Over 200 different PTMs have been described, and while they are essential for protein function, localization and stability, their dysregulation is often associated with disease conditions. PTMs can affect the proteolytic processing of proteins and prevent MHC binding, thereby changing the repertoire of peptides presented on MHC molecules. However, it is also increasingly evident that many peptides presented on MHC molecules carry PTMs, which can alter their immunogenicity. As a result, the presentation of post-translationally modified peptides by MHC molecules plays a significant role in various diseases, as well as autoimmune disorders and allergies. This review will provide an overview of the impact of PTMs on antigen presentation and their implications for immune recognition and disease.

Role models play a crucial role in inspiring and guiding careers in science, offering tangible examples of success and resilience. Reflecting on my journey from a small town in southern Chile to leading a lab at Karolinska Institutet, I've learned that relatable role models are particularly impactful for overcoming imposter syndrome and fostering a sense of belonging in academia. Early in my career, I drew inspiration from peers and mentors, gradually building my confidence and embracing my strengths. Later, exposure to interdisciplinary role models expanded my horizons and shaped my approach to science. Now, as a PI, I see my role as both a coach and mentor, fostering a team dynamic that amplifies individual strengths. Success in science often stems from fearlessness, adaptability and a willingness to seize opportunities, even when the outcome is uncertain. My journey demonstrates that good scientists can come from anywhere, including a small town in southern Chile.