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Annual Review of Immunology Apr 2023Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways,... (Review)
Review
Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.
Topics: Humans; Animals; Interferons; Lupus Erythematosus, Systemic; B-Lymphocytes; T-Lymphocytes, Helper-Inducer; Autoantibodies
PubMed: 36854182
DOI: 10.1146/annurev-immunol-101921-042422 -
Nature Jan 2020Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes. The clinical presentation of patients with different subtypes is...
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8 T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
Topics: Antibodies, Monoclonal, Humanized; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; Dendritic Cells, Follicular; Humans; Immunotherapy; Mutation; Phenotype; Prognosis; Programmed Cell Death 1 Receptor; Reproducibility of Results; Sarcoma; Survival Rate; Tertiary Lymphoid Structures; Tumor Microenvironment
PubMed: 31942077
DOI: 10.1038/s41586-019-1906-8 -
Frontiers in Immunology 2022Liver fibrosis is a common pathological feature of end stage liver failure, a severe life-threatening disease worldwide. Nonalcoholic fatty liver disease (NAFLD),... (Review)
Review
Liver fibrosis is a common pathological feature of end stage liver failure, a severe life-threatening disease worldwide. Nonalcoholic fatty liver disease (NAFLD), especially its more severe form with steatohepatitis (NASH), results from obesity, type 2 diabetes and metabolic syndrome and becomes a leading cause of liver fibrosis. Genetic factor, lipid overload/toxicity, oxidative stress and inflammation have all been implicated in the development and progression of NASH. Both innate immune response and adaptive immunity contribute to NASH-associated inflammation. Innate immunity may cause inflammation and subsequently fibrosis danger-associated molecular patterns. Increasing evidence indicates that T cell-mediated adaptive immunity also provokes inflammation and fibrosis in NASH cytotoxicity, cytokines and other proinflammatory and profibrotic mediators. Recently, the single-cell transcriptome profiling has revealed that the populations of CD4 T cells, CD8 T cells, γδ T cells, and TEMs are expanded in the liver with NASH. The activation of T cells requires antigen presentation from professional antigen-presenting cells (APCs), including macrophages, dendritic cells, and B-cells. However, since hepatocytes express MHCII molecules and costimulators, they may also act as an atypical APC to promote T cell activation. Additionally, the phenotypic switch of hepatocytes to proinflammatory cells in NASH contributes to the development of inflammation. In this review, we focus on T cells and in particular CD4 T cells and discuss the role of different subsets of CD4 T cells including Th1, Th2, Th17, Th22, and Treg in NASH-related liver inflammation and fibrosis.
Topics: CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 2; Disease Progression; Fibrosis; Humans; Inflammation; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; T-Lymphocytes, Regulatory
PubMed: 36032141
DOI: 10.3389/fimmu.2022.967410 -
Nature Cancer Jan 2023Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive census of the bone marrow...
Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive census of the bone marrow immune microenvironment in adult and pediatric patients with AML. We characterize unique inflammation signatures in a subset of AML patients, associated with inferior outcomes. We identify atypical B cells, a dysfunctional B-cell subtype enriched in patients with high-inflammation AML, as well as an increase in CD8GZMK and regulatory T cells, accompanied by a reduction in T-cell clonal expansion. We derive an inflammation-associated gene score (iScore) that associates with poor survival outcomes in patients with AML. Addition of the iScore refines current risk stratifications for patients with AML and may enable identification of patients in need of more aggressive treatment. This work provides a framework for classifying patients with AML based on their immune microenvironment and a rationale for consideration of the inflammatory state in clinical settings.
Topics: Adult; Humans; Child; Leukemia, Myeloid, Acute; Bone Marrow; T-Lymphocytes, Regulatory; Inflammation; Risk Assessment; Tumor Microenvironment
PubMed: 36581735
DOI: 10.1038/s43018-022-00480-0 -
Nature Jun 2016Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule...
Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered 'undruggable'. Fragment-based ligand discovery can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes, including those that can access regions of proteins that are difficult to target through binding affinity alone. Here we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins in human proteomes and cells. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and -10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems.
Topics: Apoptosis; Caspase 10; Caspase 8; Cells, Cultured; Cysteine; Drug Evaluation, Preclinical; Enzyme Precursors; Humans; Ligands; Peptide Fragments; Proteome; Small Molecule Libraries; T-Lymphocytes; Transcription Factors
PubMed: 27309814
DOI: 10.1038/nature18002 -
Cell Apr 2021The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely...
The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.
Topics: B-Lymphocytes; COVID-19; Cell Line; DNA Methylation; Female; Gene Silencing; Humans; Lupus Erythematosus, Systemic; RNA, Long Noncoding; Toll-Like Receptor 7; X Chromosome Inactivation
PubMed: 33735607
DOI: 10.1016/j.cell.2021.02.015 -
Zhongguo Dang Dai Er Ke Za Zhi =... Mar 2018Infectious diseases can be caused by multiple pathogens, which can produce specific immune response in human body. The immune response produced by T cells is cellular... (Review)
Review
Infectious diseases can be caused by multiple pathogens, which can produce specific immune response in human body. The immune response produced by T cells is cellular immunity, which plays an important role in the anti-infection process of human body, and can participate in immunological protection and cause immunopathology. The outcome of various infectious diseases is closely related to cellular immune function, especially the function of T cells. Jurkat cells belong to the human acute T lymphocyte leukemia cell line. Jurkat cell model can simulate the function T lymphocytes, so it is widely used in the in vitro studies of T cell signal transduction, cytokines, and receptor expression, and can provide reference and guidance for the treatment of various infectious diseases and the research on their pathogenesis. The Jurkat cell model has been widely used in the in vitro studies of viral diseases and atypical pathogens, but parasitic infection studies using the Jurkat cell model are still rare. This article reviews advances in the application of Jurkat cell model in the research on infectious diseases.
Topics: Communicable Diseases; Deltaretrovirus Infections; Enterovirus A, Human; Enterovirus Infections; Epstein-Barr Virus Infections; HIV Infections; Humans; Jurkat Cells; T-Lymphocytes
PubMed: 29530126
DOI: 10.7499/j.issn.1008-8830.2018.03.014 -
Frontiers in Immunology 2019The increasingly recognized role of different types of B cells and plasma cells in protective and pathogenic immune responses combined with technological advances have... (Review)
Review
The increasingly recognized role of different types of B cells and plasma cells in protective and pathogenic immune responses combined with technological advances have generated a plethora of information regarding the heterogeneity of this human immune compartment. Unfortunately, the lack of a consistent classification of human B cells also creates significant imprecision on the adjudication of different phenotypes to well-defined populations. Additional confusion in the field stems from: the use of non-discriminatory, overlapping markers to define some populations, the extrapolation of mouse concepts to humans, and the assignation of functional significance to populations often defined by insufficient surface markers. In this review, we shall discuss the current understanding of human B cell heterogeneity and define major parental populations and associated subsets while discussing their functional significance. We shall also identify current challenges and opportunities. It stands to reason that a unified approach will not only permit comparison of separate studies but also improve our ability to define deviations from normative values and to create a clean framework for the identification, functional significance, and disease association with new populations.
Topics: Animals; B-Lymphocytes; B-Lymphocytes, Regulatory; Cytokines; Humans; Immunity, Humoral; Immunoglobulin D; Immunoglobulin M; Immunologic Memory; Plasma Cells
PubMed: 31681331
DOI: 10.3389/fimmu.2019.02458 -
The Journal of Allergy and Clinical... Feb 2023Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid...
Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 10 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy.
Topics: Humans; Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes; CD4-Positive T-Lymphocytes; Thymus Gland; Receptors, Antigen, T-Cell
PubMed: 36456361
DOI: 10.1016/j.jaci.2022.10.022 -
Proceedings of the National Academy of... Apr 2021Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor...
Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8 T cells or macrophages eliminates the difference in tumor growth between WT and mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy.
Topics: Animals; CD8-Positive T-Lymphocytes; China; Female; Immunization; Macrophage Activation; Male; Melanoma; Mice; NF-kappa B; Neoplasms; Receptors, CCR; Signal Transduction; T-Lymphocytes; Toll-Like Receptor 4; Tumor-Associated Macrophages
PubMed: 33846258
DOI: 10.1073/pnas.2024171118