Immunology & Cell Biology最新文献

Activation of CD8⁺ T cells enable them to control virus infections and tumors. This process involves the differentiation of naïve CD8⁺ T cells into effector and memory states, driven by specific transcription factors (TFs). Previously, we have shown that Granzyme A (Gzma) induction in activated CD8⁺ T cells depends on Gata3 and the establishment of a permissive chromatin landscape at the Gzma locus. Interestingly, Gzma expression is independent of IL-4 signaling, which typically upregulates Gata3 in CD4⁺ T cells, suggesting an alternative pathway for Gata3 induction. Here we demonstrate that Notch signals during CD8⁺ T cell activation promote Gzma expression. Inhibition of Notch signaling or loss of the Notch transactivator Rbp-j leads to reduced Gzma expression, with transcriptionally repressive chromatin at the Gzma locus. The genome targets of Gata3 differ in effector CD8⁺ T cells activated with IL-4 compared with those activated with Notch signals or isolated after IAV infection. This indicates that the signals received during CD8⁺ T cell activation can alter the chromatin landscape, affecting Gata3 function. Furthermore, Gata3 deficiency results in reduced IAV-specific CD8⁺ T cell responses and decreased Gzma expression, although the Gzma locus maintains a permissive chromatin landscape. These findings suggest that Notch signals received by virus-specific CD8⁺ T cells prepare the chromatin landscape for Gata3 binding to CD8⁺ lineage-specific gene loci, promoting effective CD8⁺ T cell immunity.

Outbreaks of respiratory virus infections and arbovirus infections both pose a substantial threat to global public health. Clinically, both types of infection range from mild to severe and coinfections may occur more commonly than supposed. Our previous experimental coinfection study in mice demonstrated that prior infection with the arbovirus Semliki Forest virus (SFV) negatively impacted immune responses to influenza A virus (IAV). Here, we investigate whether simultaneous coinfection impacts the outcome of immune responses or disease. Simultaneous SFV and IAV infection did not lead to exacerbated or attenuated disease compared with the single virus infection control groups. SFV brain virus titers and brain pathology, including inflammation and immune responses, were comparable in the coinfection and single infection groups. By contrast, there was enhanced IAV replication, but no exacerbated lung pathology in coinfected mice. The magnitude of IAV-specific CD8⁺ T-cell responses in the lungs was lower compared with IAV-only infection. Considered along with our previous study, this study provides evidence that the timing of viral coinfection is pivotal in determining effects on immune responses, pathological changes and disease outcome.

Sjögren's disease (SjD) is a chronic autoimmune disorder characterized by increased circulating self-reactive B cells. While many of these self-reactive B cells emerge from the bone marrow, it is not known whether they are excluded from or enriched in specific developmental stages in the periphery. The aim of this study was to determine the immunophenotype of circulating self-reactive B cells in SjD to inform more precise therapeutic targeting. Five major B cell populations: transitional, mature naïve, switched memory, double negative and plasmablasts were single-cell sorted and cultured to produce IgG. Self-reactive IgG was identified by ELISA, flow cytometry of permeabilized HEK293 cells and HEp-2 indirect immunofluorescence. Immunoglobulin heavy chains were sequenced by Sanger and next-generation sequencing. Compared with healthy donor controls (HCs), SjD patients had higher frequencies of naïve and CD21^low atypical memory B cell subsets, while antigen-experienced B cells expressed more Ki67 and CD86. B cells recognizing intracellular self-antigens were identified in all stages of peripheral B cell development for SjD and HCs, but frequencies of autoreactive B cells were up to 10-fold higher in SjD. Self-reactive transitional B cells expressed higher surface CD38 and lower surface IgM. An increase in self-reactive B cells throughout peripheral development in SjD compared with HCs suggests that counterselection of autoantibody-bearing B cells during central and peripheral tolerance checkpoints are reduced in SjD. Therapeutic strategies focused on depleting B cells based on B cell receptor specificity rather than the developmental stage would be more efficient to target self-reactive B cells in SjD.

In this article, we discuss our experiences and perspectives in forming a workplace Parents Group. We reflect on the need for these networks, what has worked well, and the challenges we’ve experienced. We also provide some practical advice for those with parenting-related career disruptions for addressing this topic in grant applications.

We recently developed a hybrid protein, tentatively named human MIKO-1 (hMIKO-1), based on the amino acid sequences of human S100A8 (hS100A8) and hS100A9. Human THP-1 macrophages (THP-1m), differentiated from THP-1 cells by phorbol 12-myristate 13-acetate, were used to investigate the immune function of hMIKO-1 as a drug for inflammatory diseases. Western blotting was conducted to confirm whether hMIKO-1 binds with β-actin and nuclear factor-kappa B to form complexes in THP-1m. A polymerase chain reaction (PCR) and quantitative PCR were performed to examine changes in the messenger RNA levels of proinflammatory cytokines in THP-1m. Fluorescent immunochemical staining was used to observe the intracellular localization of hMIKO-1 and hS100A8 or hS100A9 in THP-1m. As observed microscopically, the intracellular localization of hMIKO-1 in THP-1m was consistent with that of hS100A8, suggesting the close involvement of hS100A8 in the intracellular behavior of hMIKO-1 in THP-1m. Western blotting revealed that hMIKO-1 formed complexes with intracellular proteins, such as β-actin and nuclear factor-kappa B, to negatively regulate inflammatory signal transduction in THP-1m. Flow cytometry showed that the binding of hMIKO-1 to THP-1m significantly decreased when THP-1m were preliminarily treated with a sialidase (neuraminidases) cocktail. Therefore, the present results strongly suggest that the binding of hMIKO-1 to THP-1m closely involves the sugar chains of the surface proteins of cells. The messenger RNA expression of each proinflammatory cytokine was significantly suppressed in THP-1m preliminarily treated with hMIKO-1 despite a subsequent stimulation with lipopolysaccharide. In conclusion, hMIKO-1 is a functional molecule that significantly inhibits inflammatory signal transduction in THP-1m.

Over the years, beginning with my undergraduate lab experiences, I became aware of the traits essential for success in academic study and research. The traits, which I refer to as the “S Triple G Traits” are Support, Growth mindset, Grit and Grace. Support can come from a person's family, friends, lab members, supervisors and themselves. A growth mindset is being open to the possibility of improving and overcoming obstacles. Grit can be considered the process of continuing to apply what you learn from reflection of having a growth mindset and setting it into practice. In theory, your growth mindset can be the foundation on which you can propel your grit in the right direction. Grace is taking a moment to acknowledge your setback and give yourself permission to honor and recognize all the effort you contributed. Using this combination of traits will help to equip students to achieve their goals when faced with obstacles.

The glycolytic enzyme, fructose-1,6-bisphosphate aldolase B (ALDOB), is recognized for its key role in shaping tthe umor immune microenvironment. However, the precise ways in which it influences the CD8⁺ T cell immune response in colorectal cancer (CRC) are still largely unknown. This study is designed to elucidate the interplay between ALDOB and the immune system in CRC. We analyzed the high expression of ALDOB in CRC tissues and cells through bioinformatics, clinical samples and in vitro experiments, finding that it promoted tumor progression. Its high expression was negatively correlated with CD8 expression and positively correlated with PDL1 expression. Further cell experiments revealed that ALDOB overexpression enhanced the expression of WNT signaling pathway-related proteins (β-catenin and c-myc), which in turn promoted PDL1 expression in CRC cells, inhibiting the proliferation and killing effect of CD8⁺ T cells in co-culture systems. Our findings disclose how ALDOB influences CD8⁺ T cell recruitment and antitumor immune function, proposing it as a potential target for the treatment of CRC.

The discourse surrounding gender equity has intensified recently, amplified by the impacts of the COVID-19 pandemic, highlighting the critical underrepresentation of women in leadership roles across various sectors including the media and healthcare. In medical research, this disparity is particularly pronounced, with women often excluded from senior positions despite their substantial presence in the workforce. This review seeks to explore the multifaceted issue of gender inequity in medical research leadership, examining the systemic barriers that women face, the socioeconomic factors that compound these challenges and the global variations in leadership representation of women. Diverse leadership teams are essential for fostering medical innovation, improving patient outcomes and ensuring that clinical trials and medical research are effective, inclusive and representative. The underrepresentation of women in leadership roles is not merely a matter of gender bias; it is intricately linked to socioeconomic factors that hinder their advancement. Women from lower socioeconomic backgrounds face additional obstacles, such as limited access to education and professional networks, which further exacerbate their underrepresentation in leadership positions. Moreover, cultural and societal norms play a significant role in shaping the career trajectories of women. As a group of immunologists, including representatives of the International Union of Immunological Sciences (IUIS) Gender Equity Committee, we review the causes of these inequities. We examine the impact of gender-diverse leadership on pre-clinical and medical research, emphasizing the need for inclusive leadership to drive progress in medical research and resulting healthcare. Finally, the review proposes strategies for improving gender equity in medical research leadership, including policy changes, organizational initiatives and societal shifts. By addressing these critical issues, this review contributes to the ongoing efforts to promote gender equity in medical research, ultimately enhancing the quality and inclusiveness of scientific inquiry and its impact on healthcare delivery.

In this article, we discuss a recent study, where autosomal monoallelic expression of genes underlying Inborn Errors of Immunity were investigated. About 2-10% of genes are predominantly transcribed from a single allele leading to autosomal random monoallelic expression (I). If this is skewed in a cell population from an individual with an autosomal dominant inborn error of immunity, this can lead to a mild to no phenotype (incomplete penetrance) if the wildtype allele is favored (II), or to more severe disease presentation if the variant allele is favored (III).

In this article, we discuss a recent article by Jia et al., where high OLAH expression was detected in severe and fatal respiratory disease which was associated with a number of processes and responses. These include high abundance of oleic acid, excessive cytokine release, high viral titres and lipid droplets and increased presence of lung-associated innate cells.