Immunology & Cell Biology最新文献

Monash Sensory Science is a scientific outreach initiative specifically tailored to members of the community who are blind, have low vision and have diverse needs. The purpose of this initiative is to showcase Australian science and encourage greater participation in science from these often-overlooked communities. This article presents our experience in establishing Monash Sensory Science at Monash University and inspiring other institutions to launch similar outreach events.

We explored the frequency of CD14⁻CD10⁻CD45⁺HLA-DR⁻SSC⁺⁺ neutrophils (CD10⁻ neutrophils) in patients with non-Hodgkin's lymphoma (NHL), and their immunologic characteristics and clinical significance. Patients with NHL who were newly diagnosed (NDP; n = 33), in remission (RMP; n = 28) and relapsed (RLP; n = 29) were included, and 47 volunteers were recruited as healthy controls (HCs). The frequency of CD10⁻ neutrophils in the peripheral blood from HC and patients with NHL was detected. CD10⁻ and CD10⁺ neutrophils were sorted, and their cytology was analyzed. CD3⁺ T cells were also isolated and cultured with the autologous CD10⁻ or CD10⁺ neutrophils, after which the proliferation and death rates of T cells were determined. The levels of arginase-1 (Arg-1) and reactive oxygen species (ROS) in CD10⁺ or CD10⁻ neutrophils were examined. Few CD10⁻ neutrophils were detected in HCs but were significantly elevated in patients with NHL, especially in NDP and RLP. In addition, CD10⁻ neutrophils in NDP with advanced stage and high risk were markedly higher than those in NDP with limited stage and low risk. In RMP and RLP, the relapse-free survival and overall survival in patients with high CD10⁻ neutrophils were shorter than those with low CD10⁻ neutrophils. CD10⁻ neutrophils from patients with NHL, which mainly consist of immature neutrophils, inhibit T-cell proliferation and facilitate T-cell death. Furthermore, a significant increase was observed in Arg-1 expression, along with an increase to a certain extent in ROS. CD10⁻ neutrophils in patients with NHL have characteristics of myeloid-derived suppressor cells and may be related to disease progression and poor prognosis.

CD4⁺ forkhead box P3 (FOXP3)⁺ regulatory T cells (Tregs) are essential in maintaining immune tolerance and suppressing excessive immune responses. Tregs also contribute to tissue repair processes distinct from their roles in immune suppression. For these reasons, Tregs are candidates for targeted therapies for inflammatory and autoimmune diseases, and in diseases where tissue damage occurs. MT-2 cells, an immortalized Treg-like cell line, offer a model to study Treg biology and their therapeutic potential. In the present study, we use clustered regularly interspaced palindromic repeats (CRISPR)-mediated knockdown of FOXP3 in MT-2 cells to understand the transcriptional and functional changes that occur when FOXP3 is lost and to compare MT-2 cells with primary human Tregs. We demonstrate that loss of FOXP3 affects the transcriptome of MT-2 cells and that FOXP3's potential downstream targets include a wide range of transcripts that participate in the cell cycle, promote growth and contribute to inflammatory processes, but do not wholly simulate previously reported human primary Treg transcriptional changes in the absence of FOXP3. We also demonstrate that FOXP3 regulates cell cycling and proliferation, expression of molecules crucial to Treg function and MT-2 cell–suppressive activities. Thus, MT-2 cells offer opportunities to address regulatory T-cell functions in vitro.

T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL-4 reporter mice in culture and in vivo following exposure to type 2 immunogens. In culture, Il4 alleles had independent, heritable expression probabilities. Modeling showed that in co-expressors, dual allele transcription occurs for only short periods, limiting per-cell mRNA variation in individual cells within a population of Th2 cells. In vivo profiles suggested that early in the immune response, IL-4 output was derived predominantly from single alleles, but co-expression became more frequent over time and were tuned by STAT6, supporting the probabilistic regulation of Il4 alleles in vivo among committed IL-4 producers. We suggest an imprinted probability of expression from individual alleles with a short transcriptional shutoff time controls the magnitude of T cell IL-4 output, but the amount produced per allele is amplified by STAT6 signaling. This form of regulation may be a relevant general mechanism governing cytokine expression.

Therapy-induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc-1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence-associated β-galactosidase, p21^Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence-associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement-related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b-9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.

In this article, we discuss a recently published article that demonstrated a novel way of identifying viral pathogens reactivating in human cells to be used as cellular therapy, in this instance chimeric antigen receptor (CAR) T cells. The authors used search engines and databases to identify viruses able to reactivate in T cells and then tested this initially in T-cell cultures, specifically human herpesvirus 6. This virus was then shown to reactivate infrequently in vitro and in vivo in CAR T cells as a consequence of T-cell activation. The methodology may be most clinically useful for more frequently reactivating viruses in other types of cellular therapy such as allogenic CAR T cells or induced pluripotent stem cells.

Cancer immunotherapy has been rejuvenated by the growing understanding of the immune system's role in tumor activity over the past two decades. During cancer initiation and progression, tumor cells employ various mechanisms that resemble peripheral immune tolerance to evade the antitumor responses of the immune system. Immune checkpoint molecules are the major mechanism of immune resistance that are exploited by tumor cells to inhibit T-cell activation and suppress immune responses. The targeting of immune checkpoint pathways has led to substantial improvements in survival rates in a number of solid cancers. However, a lack of understanding of the heterogeneity of the tumor microenvironment (TME) has resulted in inefficient therapy responses. A greater understanding of the TME is needed to identify patients likely to respond, and those that will have resistance to immune checkpoint inhibitors (ICIs). Advancement in spatial single-cell technologies has allowed deeper insight into the phenotypic and functional diversities of cells in the TME. In this review, we provide an overview of ICI biomarkers and highlight how high-dimensional spatially resolved, single-cell approaches provide deep molecular insights into the TME and allow for the discovery of biomarkers of clinical benefit.

Immunology research holds significant potential for enhanced inclusivity at the beginning of the science literacy journey, but persistent challenges stem from limited awareness that improvement is needed in this field. At the 2023 Monash Sensory Science Exhibition, we had the opportunity to present several tactile posters, using simple materials, for visually impaired participants to showcase our research on the pathogenesis of rheumatoid arthritis as a result of immune tolerance breakdown and liposome-based tolerogenic immunotherapy. The posters stimulated lively discussions about autoimmune arthritic diseases and our research. With consideration of the diversity of the participants, the efforts of scientists in promoting science literacy for the community can promote a more inclusive environment and engage and inspire a broader audience.

Vimentin, an intermediate filament protein primarily recognized for its intracellular role in maintaining cellular structure, has recently garnered increased attention and emerged as a pivotal extracellular player in immune regulation and host–pathogen interactions. While the functions of extracellular vimentin were initially overshadowed by its cytoskeletal role, accumulating evidence now highlights its significance in diverse physiological and pathological events. This review explores the multifaceted role of extracellular vimentin in modulating immune responses and orchestrating interactions between host cells and pathogens. It delves into the mechanisms underlying vimentin's release into the extracellular milieu, elucidating its unconventional secretion pathways and identifying critical molecular triggers. In addition, the future perspectives of using extracellular vimentin in diagnostics and as a target protein in the treatment of diseases are discussed.

Immunology & Cell Biology celebrated its 100-year birthday as a journal with an editorial workshop focused on how we can improve the author experience. In our renewed editorial policies, we articulate our editorial focus on the quality of the scientific question and the robustness of the conclusions, including a new “scoop protection” policy to live our values. The journal is dedicated to maintaining its relationship with reviewers, enabling rapid quality peer review, but is also opening new lines of submission with expedited cross-platform assessment of reviews and incorporation into the Review Commons submission pipeline. In 2024 we will expand our social media promotion of articles and build on the career development resource of Immunology Futures. Here we lay out the ethos, numbers and rationale behind ICB's renewed author-centric publication policies for 2024.