Immunology & Cell Biology最新文献

Resident macrophages of various mammalian organs are characterized by several distinctive features in their gene expression profile and phenotype, including involvement in the regulation of organ functions, as well as reduced sensitivity to proinflammatory activation factors. The reasons for the formation of such a specific phenotype remain the subject of intensive research. Some papers emphasize the role of the origin of organ macrophages. Other studies indicate that monocytes that develop in the red bone marrow are also able to form resident macrophages with a phenotype characteristic of a particular organ, but this requires appropriate microenvironmental conditions. In this article, we studied the possibility of differentiation of monocyte-derived macrophages into cells with a Kupffer-like phenotype under the influence of the main stromal components of Kupffer cells macrophage niche: Ito cells, liver sinusoid endotheliocytes and hepatocyte growth factor (HGF). It was found that Kupffer cells are characterized by several features, including increased expression of transcription factors Spic and Id3, as well as MUP family genes, Clusterin and Ngp genes. In addition, Kupffer cells were characterized by a higher proliferative activity. The expression of marker genes of Kupffer cells (i.e. Id3, Spic, Marco and Timd4) increased in monocyte-derived macrophages during coculture with Ito cells, liver sinusoid endothelial cells, macrophage colony–stimulating factor and HGF cells only by 3 days. However, the expression level of these genes was always higher in Kupffer cells. In addition, a complete coincidence of the expressed gene profile in monocyte-derived macrophages and Kupffer cells did not occur even after 3 days of culturing.

The significance of metabolites in orchestrating immune cells is now recognized to be on par with other key immune modulators, such as cytokines or chemokines. Seminal discoveries have now been built upon with discoveries that have acted to take the discipline to new heights, particularly in T-cell immunity. This accelerated progress has uncovered a plethora of opportunities for pharmacological intervention, with the aim of harnessing immunometabolism for refined immune modulation across several pathologies. This Research Highlight focuses on the latest breakthroughs during 2023 from the preceding year that provide mechanistic insight, as well as viable translational opportunities, in the field of T-cell immunometabolism.

In 2023, several significant discoveries on the function of microRNAs in the immune system were reported. Here we discuss several notable papers that revealed important functions in T cells.

Epigenetic modifications, particularly through methylation of DNA packaging histones, play a pivotal role in controlling gene expression. Aberrant patterns of histone methylation have been associated with the development and progression of hematological malignancies. Unraveling the impact of aberrant histone marks on gene expression and leukemogenesis has spurred a concerted effort to develop clinically effective epigenetic therapies. In malignancies associated with the accumulation of histone H3 lysine trimethylation (H3K27me3), one such intervention involves preventing the deposition of this repressive histone mark by inhibiting the histone-modifying enzymes EZH1 and EZH2. While inhibition of EZH1/2 has demonstrated efficacy in both preclinical studies and clinical trials in various cancers, studies delineating the dynamic effect of EZH1/2 inhibition on H3K27me3 and disease relapse in clinical samples are lacking. In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.

Mentorship refers to the guidance given by a mentor to a less experienced individual to enhance their professional and personal development. For graduate research students, seeking independent mentors external to their institution offers the rewarding opportunity to obtain objective guidance on a variety of work, study and life matters. This article outlines the steps taken to develop a professional society-based, international mentoring program of over 70 participants. This 6-month program aimed to connect graduate research students with more senior academic scientists in response to the limited networking opportunities imposed by the coronavirus disease 2019 (COVID-19) pandemic in Australia. Outlined here are the resources used to maximize the potential of this successful program, which include (1) an ‘Introduction to Mentoring’ workshop, (2) the use of a mentoring software or communication strategy to maintain program momentum and (3) the integration of in-person networking events. Overall, the program was a great success, with a high satisfaction rating (8.7/10) and a large number of participants reported that they would maintain their mentoring relationship. All participants stated that they would recommend the program to a peer, and thus reiterations of the program would likely be similarly well-received and beneficial to the Australasian immunology community.

Staphylococcus aureus is a significant bacterial pathogen in both community and hospital settings, and the escalation of antimicrobial-resistant strains is of immense global concern. Vaccination is an inviting long-term strategy to curb staphylococcal disease, but identification of an effective vaccine has proved to be challenging. Three well-characterized, ubiquitous, secreted immune evasion factors from the staphylococcal superantigen-like (SSL) protein family were selected for the development of a vaccine. Wild-type SSL3, 7 and 11, which inhibit signaling through Toll-like receptor 2, cleavage of complement component 5 and neutrophil function, respectively, were successfully combined into a stable, active fusion protein (PolySSL7311). Vaccination of mice with an attenuated form of the PolySSL7311 protein stimulated significantly elevated specific immunoglobulin G and splenocyte proliferation responses to each component relative to adjuvant-only controls. Vaccination with PolySSL7311, but not a mixture of the individual proteins, led to a > 10² reduction in S. aureus tissue burden compared with controls after peritoneal challenge. Comparable antibody responses were elicited after coadministration of the vaccine in either AddaVax (an analog of MF59) or an Alum-based adjuvant; but only AddaVax conferred a significant reduction in bacterial load, aligning with other studies that suggest both cellular and humoral immune responses are necessary for protective immunity to S. aureus. Anti-sera from mice immunized with PolySSL7311, but not individual proteins, partially neutralized the functional activities of SSL7. This study confirms the importance of these SSLs for the survival of S. aureus in vivo and suggests that PolySSL7311 is a promising vaccine candidate.

Age-associated B cells (ABCs) are a stable subset of memory B lymphocytes that develop during microbial infections and in autoimmune diseases. Despite growing appreciation of their phenotypic and functional characteristics, the transcriptional networks involved in ABC fate commitment and maintenance have remained elusive. In their recent publication, Dai et al. tackle this problem, leveraging both mouse models and human diseases to reveal zinc finger E-box-binding homeobox 2 (ZEB2) as a key transcriptional regulator of ABC lineage specification. In aggregate, their results show that ZEB2, a member of the zinc finger E homeobox binding family, promotes ABC differentiation by repressing alternative differentiative fates and targeting genes important for ABC character and function. Moreover, their results strengthen the case for causal links between ABC fate and function in autoimmune pathologies.

Science communication is often confined to spoken, written or graphical form, neglecting the integration of other tools that would open inclusive scientific dialog to the low-vision community. To address this barrier, members from the Monash Rheumatology clinical and laboratory research groups formed a Lupus Sensory Science team to create a breakout room at the 2023 Monash Sensory Science Exhibit on Autoimmunity. Our goal was to develop multimodal displays and artworks to engage participants with blindness and low vision with the immunological underpinnings of systemic lupus erythematosus (SLE). Here I describe how we created several stations using a combination of tactile posters and models to communicate disease manifestations and immune system dysregulation in SLE. I reflect on how participants keenly engaged with our artworks, asking thoughtful questions that stimulated interesting discussions about treatment options in SLE. In addition, I analyze how our exhibit could be improved to further increase accessibility for the low-vision community. Overall, we learned a lot about how to be inclusive in scientific communication methods and we will strive to continue to engage all members of our community in scientific discussion.

Immunologists are very social people—they love to meet other immunologists and talk about immunology (and immunologists). Constantly! γδ T-cell researchers are no exception. On the contrary, as there are not so many of them compared to, say, researchers working on dendritic cells, they especially crave frequent interactions with like-minded scientists. This is where the technological solutions being developed during the coronavirus disease 2019 (COVID-19) pandemic come into play that have, almost overnight, allowed researchers to hold meetings and lectures online. We here describe how we set up the virtual ‘γδ T Cell Club’, a monthly webinar series that aims to bring the field closer together, and present our musings about what we have learned from this experience, which we hope is useful for other researchers interested in connecting online.

Fibroblastic reticular cells (FRCs) construct microanatomical niches that support lymph node (LN) homeostasis and coordination of immune responses. Transcription factors regulating the functionality of FRCs remain poorly understood. Here, we investigated the role of the transcription factor SpiB that is expressed in LN FRCs. Conditional ablation of SpiB in FRCs impaired the FRC network in the T-cell zone of LNs, leading to reduced numbers of FRCs and altered homeostatic functions including reduced CCL21 and interleukin-7 expression. The size and cellularity of LNs remained intact in the absence of SpiB but the space between the reticular network increased, indicating that although FRCs were reduced in number they stretched to maintain network integrity. Following virus infection, antiviral CD8⁺ T-cell responses were impaired, suggesting a role for SpiB expression in FRCs in orchestrating immune responses. Together, our findings reveal a new role for SpiB as an important regulator of FRC functions and immunity in LNs.