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Nature Jul 2023The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour...
The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.
Topics: Animals; Mice; B-Lymphocytes; Lymphocyte Activation; Melanoma; T-Lymphocytes; Flow Cytometry; Melanoma, Experimental; Lymph Nodes; Antigen Presentation; Receptors, Antigen, B-Cell; Single-Cell Gene Expression Analysis; Tumor Burden; Interferon Type I
PubMed: 37344597
DOI: 10.1038/s41586-023-06231-0 -
Nature Reviews. Immunology Jul 2023'Glomerulonephritis' (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the... (Review)
Review
'Glomerulonephritis' (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.
Topics: Humans; Glomerulonephritis; Adaptive Immunity; Immunity, Innate; Cytokines; Immunotherapy
PubMed: 36635359
DOI: 10.1038/s41577-022-00816-y -
Frontiers in Immunology 2023Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime... (Review)
Review
Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.
Topics: Immunotherapy; Immunomodulation; Immunity, Active; Immunotherapy, Adoptive; Adoptive Transfer; Neoplasms
PubMed: 37691932
DOI: 10.3389/fimmu.2023.1212476 -
Cell Apr 2024Adaptive immunity provides protection against infectious and malignant diseases. These effects are mediated by lymphocytes that sense and respond with targeted precision... (Review)
Review
Adaptive immunity provides protection against infectious and malignant diseases. These effects are mediated by lymphocytes that sense and respond with targeted precision to perturbations induced by pathogens and tissue damage. Here, we review key principles underlying adaptive immunity orchestrated by distinct T cell and B cell populations and their extensions to disease therapies. We discuss the intracellular and intercellular processes shaping antigen specificity and recognition in immune activation and lymphocyte functions in mediating effector and memory responses. We also describe how lymphocytes balance protective immunity against autoimmunity and immunopathology, including during immune tolerance, response to chronic antigen stimulation, and adaptation to non-lymphoid tissues in coordinating tissue immunity and homeostasis. Finally, we discuss extracellular signals and cell-intrinsic programs underpinning adaptive immunity and conclude by summarizing key advances in vaccination and engineering adaptive immune responses for therapeutic interventions. A deeper understanding of these principles holds promise for uncovering new means to improve human health.
Topics: Humans; Adaptive Immunity; Animals; B-Lymphocytes; T-Lymphocytes; Autoimmunity
PubMed: 38670065
DOI: 10.1016/j.cell.2024.03.037 -
Viruses Jun 2023Since its discovery, Porcine reproductive and respiratory syndrome (PRRS) has had a huge impact on the farming industry. The virus that causes PRRS is Porcine... (Review)
Review
Since its discovery, Porcine reproductive and respiratory syndrome (PRRS) has had a huge impact on the farming industry. The virus that causes PRRS is Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), and because of its genetic diversity and the complexity of the immune response, the eradication of PRRS has been a challenge. To provide scientific references for PRRSV control and vaccine development, this study describes the processes of PRRSV-induced infection and escape, as well as the host adaptive immune response to PRRSV. It also discusses the relationship between PRRSV and the adaptive immune response.
Topics: Swine; Animals; Porcine respiratory and reproductive syndrome virus; Porcine Reproductive and Respiratory Syndrome; Adaptive Immunity; Viral Vaccines; Antibodies, Viral
PubMed: 37515130
DOI: 10.3390/v15071442 -
Immunity Aug 2023Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the...
Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract.
Topics: Humans; Influenza Vaccines; Antibody Formation; Antibodies, Viral; T-Lymphocytes; Antigens; Organoids; Influenza, Human
PubMed: 37478854
DOI: 10.1016/j.immuni.2023.06.019 -
Science China. Life Sciences Jul 2023With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between... (Review)
Review
With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.
Topics: Humans; Autoimmune Diseases; Immunity, Innate; Autoimmunity; Adaptive Immunity; Genetic Predisposition to Disease
PubMed: 36738430
DOI: 10.1007/s11427-021-2187-3 -
Cell Apr 2024Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is... (Review)
Review
Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is termed adaptive immunity, which involves the exquisitely specific activities of lymphocytes. But the other arm of immunity, so-called "innate immunity," had been neglected. To celebrate Cell's 50 anniversary, we have put together a review of the processes and components of innate immunity and trace the seminal contributions leading to the modern state of this field. Innate immunity has joined adaptive immunity in the center of interest for all those who study the body's defenses, as well as homeostasis and pathology. We are now entering the era where therapeutic targeting of innate immune receptors and downstream signals hold substantial promise for infectious and inflammatory diseases and cancer.
Topics: Immunity, Innate; Humans; Animals; History, 20th Century; History, 21st Century; Adaptive Immunity; Allergy and Immunology
PubMed: 38670064
DOI: 10.1016/j.cell.2024.03.036 -
Science (New York, N.Y.) Jun 2023During initiation of antiviral and antitumor T cell-mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex...
During initiation of antiviral and antitumor T cell-mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex (MHC) class I molecules. Cross-presentation relies on the unusual "leakiness" of endocytic compartments in DCs, whereby internalized proteins escape into the cytosol for proteasome-mediated generation of MHC I-binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched for cell type-specific effectors of endocytic escape. We devised an assay suitable for genetic screening and identified a pore-forming protein, perforin-2 (), as a dedicated effector exclusive to cross-presenting cells. Perforin-2 was recruited to antigen-containing compartments, where it underwent maturation, releasing its pore-forming domain. mice failed to efficiently prime CD8 T cells to cell-associated antigens, revealing an important role for perforin-2 in cytosolic entry of antigens during cross-presentation.
Topics: Animals; Mice; Antigen Presentation; Antigens; CD8-Positive T-Lymphocytes; Cross-Priming; Dendritic Cells; Endocytosis; Genetic Testing; Histocompatibility Antigens Class I; Pore Forming Cytotoxic Proteins; Proteolysis
PubMed: 37347855
DOI: 10.1126/science.adg8802 -
Nature Feb 2024Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability. However, the variables that drive...
Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability. However, the variables that drive such differences in cytokine secretion-a crucial component of the host response to immune challenges-remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.
Topics: Female; Humans; Male; Adaptive Immunity; Autoimmune Diseases; Body Mass Index; Cytokines; Cytomegalovirus; DNA Methylation; Epigenesis, Genetic; Immunity, Innate; Infections; Neoplasms; Signal Transduction; Smoking
PubMed: 38355791
DOI: 10.1038/s41586-023-06968-8