Cellular immunology最新文献

Vγ9Vδ2 T lymphocytes are programmed for broad antimicrobial responses with rapid production of Th1 cytokines even before birth, and thus thought to play key roles against pathogens in infants. The process regulating Vδ2 cell acquisition of cytotoxic potential shortly after birth remains understudied. We observed that perforin production in cord blood Vδ2 cells correlates with phenotypes defined by the concomitant assessment of PD-1 and CD56. Bulk RNA sequencing of sorted Vδ2 cell fractions indicated that transcripts related to cytotoxic activity and NK function are enriched in the subset with the highest proportion of perforin⁺ cells. Among differentially expressed transcripts, IRF8, previously linked to CD8 T cell effector differentiation and NK maturation, has the potential to mediate Vδ2 cell differentiation towards cytotoxic effectors. Our current and past results support the hypothesis that distinct mechanisms regulate Vδ2 cell cytotoxic function before and after birth, possibly linked to different levels of microbial exposure.

At present, recipients of allogeneic hematopoietic stem-cells are still suffering from recurrent infections after transplantation. Infusion of virus-specific T cells (VST) post-transplant reportedly fights several viruses without increasing the risk of de novo graft-versus-host disease. This study targeted cytomegalovirus (CMV) for the development of an innovative approach for generating a very specific VST product following Good Manufacturing Practices (GMP) guidelines.

We used a sterile disposable compartment named the Leukoreduction System Chamber (LRS-chamber) from the apheresis platelet donation kit as the starting material, which has demonstrated high levels of T cells. Using a combination of IL-2 and IL-7 we could improve expansion of CMV-specific T cells. Moreover, by developing and establishing a new product protocol, we were able to stimulate VST proliferation and favors T cell effector memory profile. The expanded VST were enriched in a closed automated system, creating a highly pure anti-CMV product, which was pre-clinically tested for specificity in vitro and for persistence, biodistribution, and toxicity in vivo using NOD scid mice. Our results demonstrated very specific VST, able to secrete high amounts of interferon only in the presence of cells infected by the human CMV strain (AD169), and innocuous to cells partially HLA compatible without viral infection.

Newborns, whether born prematurely or at term, have a fully formed but naive immune system that must adapt to the extra-uterine environment to prevent infections. Maternal immunity, transmitted through the placenta and breast milk, protects newborns against infections, primarily via immunoglobulins (IgG and IgA) and certain maternal immune cells also known as microchimeric cells.

Recently, it also appeared that the maternal gut microbiota played a vital role in neonatal immune maturation via microbial compounds impacting immune development and the establishment of immune tolerance.

In this context, maternal vaccination is a powerful tool to enhance even more maternal and neonatal health. It involves the transfer of vaccine-induced antibodies to protect both mother and child from infectious diseases.

In this work we review the state of the art on maternal immune factors involved in the prevention of neonatal bacterial infections, with particular emphasis on the role of maternal vaccination in protecting neonates against bacterial disease.

Recent advances in immunotherapy have not addressed the challenge presented by ovarian cancer. Although the peritoneum is an “accessible” locus for this disease there has been limited characterization of the immunobiology therein. We investigated the ID8-C57BL/6J ovarian cancer model and found marked depletion of B1 cells from the ascites of the peritoneal cavity. There was also selective loss of the B1 and marginal zone B cell subsets from the spleen. Immunity to antigens that activate these subsets validated their loss rather than relocation. A marked influx of myeloid-derived suppressor cells correlated with B cell subset depletion. These observations are discussed in the context of the housekeeping burden placed on innate B cells during ovarian cancer and to foster consideration of B cell biology in therapeutic strategies to address this challenge.

Antigenic peptides play a central role in immune surveillance in cancer, infectious disease, autoimmunity, and allergy. The identification and isolation of antigenic peptides for T cell immune response are crucial for successful personalized adoptive immune cell therapy. The mainly methods includes gene sequencing and bioinformatic analysis. The antigenic peptides which identified by analysis and artificially synthesized still need antigen presenting cell (APC) to deliver to T cells. However, high costs and lengthy process times have limited its application in clinical practice. In order to overcome it, this study attempted to directly capture antigenic peptide-major histocompatibility complex (MHC) class I (pMHCs) from cell lysates using streptavidin Dynabeads and biotin-labeled antibodies, then the pMHCs was co-cultured with tumor infiltrating lymphocytes (TILs) of the same tissue origin. The results indicated that the captured pMHCs were able to enrich the tumor antigen-specific CD8⁺ T cells, and also effectively induce proliferation and cytotoxic responses of CD8⁺ T cells. This study provided a novel approach for obtaining tumor antigenic pMHCs, which could enrich antigen-specific CD8⁺ T cells, and could also function as artificial APCs (aAPCs) to stimulate proliferation and activation of T cells. Notably, these pMHCs can stimulate the proliferation of stem-like memory T cells. In conclusion, this study describes a time-saving and low-cost method to isolate tumour antigen peptide MHC complexs, helping tumor antigen-specific T cell enrichment, activation, and proliferation.

Regulatory T (Treg) cells interact with a variety of resident cells and infiltrated immune cells in the central nervous system (CNS) to modulate neuroinflammation and neurodegeneration. Extracellular amyloid-β (Aβ) peptide deposition and secondary persistent inflammation due to activation of microglia, astrocytes, and infiltrated immune cells contribute to Alzheimer's disease (AD)-related neurodegeneration. The majority of evidence supports the neuroprotective effects of Treg cells in AD. In the early stages of AD, appropriate Treg cell activity is required for the induction of microglia and astrocyte phagocytic activity in order to clear A deposits and prevent neuroinflammation. Such neuroprotective impacts were in part attributed to the ability of Treg cells to suppress deleterious and/or boost beneficial functions of microglia/astrocytes. In the later stages of AD, an effective Treg cell activity needs to prevent neurotoxicity and neurodegeneration. Treg cells can exert preventive effects on Th1-, and Th17 cell-related pathologic responses, whilst potentiating Th2-mediated protective activity. The impaired Treg cell-related immunomodulatory mechanisms have been described in AD patients and in related animal models which can contribute to the onset and progression of AD. This review aimed to provide a comprehensive figure regarding the role of Treg cells in AD while highlighting potential therapeutic approaches.

Type I interferons (IFN), especially human IFN alpha (IFNα), have been utilized for antitumor therapy for decades. Human interferon beta (IFNβ) is rarely used for cancer treatment, despite advantages over IFNα in biological activities such as tumor growth inhibition and dendritic cell (DC) activation. The utilization of pegylated human IFNβ (PEG-IFNβ), as monotherapy or in combination with immune checkpoint inhibitors (ICIs) was evaluated in this study through in vivo efficacy studies in syngeneic mouse melanoma, non-small cell lung cancer (NSCLC), and colon adenocarcinoma (COAD) models resistant to immune checkpoint inhibitors (ICIs). In vitro comparative study of PEG-IFNβ and pegylated IFNα-2b was performed in terms of tumor growth inhibition against human melanoma, NSCLC and COAD cell lines and activation of human monocyte-derived DCs (MoDCs). Our data demonstrate that the in vivo antitumor effects of PEG-IFNβ are partially attributable to tumor growth-inhibitory effects and DC-activating activities, superior to pegylated IFNα-2b. Our findings suggest that utilizing PEG-IFNβ as an antitumor therapy can enhance the therapeutic effect of ICIs in ICI-resistant tumors by directly inhibiting tumor growth and induction of DC maturation.

Inflammatory bowel diseases are associated with dysregulated inflammatory immune responses in the gastrointestinal tract. We found that deficiencies of both IL-4 receptor alpha chain (IL-4Rα) and IL-10 in BALB/c mice (IL-4Rα × IL-10 KO mice) highly induced spontaneous rectal prolapse and diarrhea. These mice also exhibited severe colitis in their cecum and colon and marked elevation of serum proinflammatory cytokines including TNFα and IFNγ. These pathologies were transmittable with their cecal contents containing Helicobacter spp. Their mesenteric LN cells produced TNFα and IFNγ in response to soluble H. hepaticus antigens and high titers of H. hepaticus-specific serum IgG were also detected. These results suggested the important function of IL-4Rα signaling in controlling the intestinal inflammation and the susceptibility to intestinal microbes including H. hepaticus. Therefore, these IL-4Rα × IL-10 KO mice potentially provide the significant murine model for clarifying the causes and control of spontaneous colitis and intestinal inflammation.

Wiskott-Aldrich syndrome (WAS) is a disorder characterized by rare X-linked genetic immune deficiency with mutations in the Was gene, which is specifically expressed in hematopoietic cells. The spleen plays a major role in hematopoiesis and red blood cell clearance. However, to date, comprehensive analyses of the spleen in wild-type (WT) and WASp-deficient (WAS-KO) mice, especially at the transcriptome level, have not been reported. In this study, single-cell RNA sequencing (scRNA-seq) was adopted to identify various types of immune cells and investigate the mechanisms underlying immune deficiency. We identified 30 clusters and 10 major cell subtypes among 11,269 cells; these cell types included B cells, T cells, dendritic cells (DCs), natural killer (NK) cells, monocytes, macrophages, granulocytes, stem cells and erythrocytes. Moreover, we evaluated gene expression differences among cell subtypes, identified differentially expressed genes (DEGs), and performed enrichment analyses to identify the reasons for the dysfunction in these different cell populations in WAS. Furthermore, some key genes were identified based on a comparison of the DEGs in each cell type involved in specific and nonspecific immune responses, and further analysis showed that these key genes were previously undiscovered pathology-related genes in WAS-KO mice. In summary, we present a landscape of immune cells in the spleen of WAS-KO mice based on detailed data obtained at single-cell resolution. These unprecedented data revealed the transcriptional characteristics of specific and nonspecific immune cells, and the key genes were identified, laying a foundation for future studies of WAS, especially studies into novel and underexplored mechanisms that may improve gene therapies for WAS.

Allergic airway diseases are caused by inappropriate immune responses directed against inhaled environmental antigens. We previously reported that the inhibition of diacylglycerol (DAG) kinase ζ (DGKζ), an enzyme that terminates DAG-mediated signaling, protects against T cell-mediated allergic airway inflammation by blocking Th2 cell differentiation. In this study, we tested whether DGKζ deficiency also affects allergic airway disease mediated by type 2 innate lymphoid cells (ILC2)s. DGKζ-deficient mice displayed diminished ILC2 function and reduced papain-induced airway inflammation compared to wildtype mice. Unexpectedly, however, mice with hematopoietic cell-specific deletion of DGKζ displayed intact airway inflammation upon papain challenge. Rather, bone marrow chimera studies revealed that DGKζ deficiency in the non-hematopoietic compartment was responsible for the reduction in papain-induced airway inflammation. These data suggest that DGK might represent a novel therapeutic target not only for T cell-dependent but also ILC2-dependent allergic airway inflammation by affecting non-hematopoietic cells.