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Clinical & Developmental Immunology 2012CD4⁺T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4⁺T cells are activated after interaction with antigen-MHC complex... (Review)
Review
CD4⁺T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4⁺T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment. Besides the classical T-helper 1 and T-helper 2, other subsets have been identified, including T-helper 17, regulatory T cell, follicular helper T cell, and T-helper 9, each with a characteristic cytokine profile. For a particular phenotype to be differentiated, a set of cytokine signaling pathways coupled with activation of lineage-specific transcription factors and epigenetic modifications at appropriate genes are required. The effector functions of these cells are mediated by the cytokines secreted by the differentiated cells. This paper will focus on the cytokine-signaling and the network of transcription factors responsible for the differentiation of naive CD4⁺T cells.
Topics: Animals; Cell Differentiation; Cytokines; Epigenesis, Genetic; Gene Expression Regulation; Humans; Lymphocyte Activation; Mice; Signal Transduction; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Th2 Cells; Transcription Factors
PubMed: 22474485
DOI: 10.1155/2012/925135 -
Cold Spring Harbor Perspectives in... Oct 2018Naïve CD4 T cells, on activation, differentiate into distinct T helper (Th) subsets that produce lineage-specific cytokines. By producing unique sets of cytokines,... (Review)
Review
Naïve CD4 T cells, on activation, differentiate into distinct T helper (Th) subsets that produce lineage-specific cytokines. By producing unique sets of cytokines, effector Th subsets play critical roles in orchestrating immune responses to a variety of infections and are involved in the pathogenesis of many inflammatory diseases including autoimmunity, allergy, and asthma. The differentiation of Th cells relies on the strength of T-cell receptor (TCR) signaling and signals triggered by polarizing cytokines that activate and/or up-regulate particular transcription factors. Several lineage-specific master transcription factors dictate Th cell fates and functions. Although these master regulators cross-regulate each other, their expression can be dynamic. Sometimes, they are even coexpressed, resulting in massive Th-cell heterogeneity and plasticity. Similar regulation mediated by these master regulators is also found in innate lymphoid cells (ILCs) that are innate counterparts of Th cells.
Topics: Animals; Cell Differentiation; Gene Expression Regulation; Humans; Inflammation; Lymphocyte Activation; T-Lymphocytes, Helper-Inducer
PubMed: 28847903
DOI: 10.1101/cshperspect.a030338 -
Nature Reviews. Immunology May 2018Upon stimulation, small numbers of naive CD8 T cells proliferate and differentiate into a variety of memory and effector cell types. CD8 T cells can persist for years... (Review)
Review
Upon stimulation, small numbers of naive CD8 T cells proliferate and differentiate into a variety of memory and effector cell types. CD8 T cells can persist for years and kill tumour cells and virally infected cells. The functional and phenotypic changes that occur during CD8 T cell differentiation are well characterized, but the epigenetic states that underlie these changes are incompletely understood. Here, we review the epigenetic processes that direct CD8 T cell differentiation and function. We focus on epigenetic modification of DNA and associated histones at genes and their regulatory elements. We also describe structural changes in chromatin organization that affect gene expression. Finally, we examine the translational potential of epigenetic interventions to improve CD8 T cell function in individuals with chronic infections and cancer.
Topics: Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Cellular Reprogramming Techniques; Chromatin Assembly and Disassembly; DNA Methylation; Enhancer Elements, Genetic; Epigenesis, Genetic; Histone Code; Humans; Immunotherapy; Models, Genetic; Models, Immunological; Transcription, Genetic
PubMed: 29379213
DOI: 10.1038/nri.2017.146 -
Science Immunology Sep 2023Thirty years of foundational research investigating molecular and cellular mechanisms promoting T cell exhaustion are now enabling rational design of T cell-based... (Review)
Review
Thirty years of foundational research investigating molecular and cellular mechanisms promoting T cell exhaustion are now enabling rational design of T cell-based therapies for the treatment of chronic infections and cancer. Once described as a static cell fate, it is now well appreciated that the developmental path toward exhaustion is composed of a heterogeneous pool of cells with varying degrees of effector potential that ultimately converge on a terminally differentiated state. Recent description of the developmental stages along the differentiation trajectory of T cell exhaustion has provided insight into past immunotherapeutic success and future opportunities. Here, we discuss the hallmarks of distinct developmental stages occurring along the path to T cell dysfunction and the impact of these discrete CD8 T cell fates on cancer immunotherapy.
Topics: T-Cell Exhaustion; Cell Differentiation; CD8-Positive T-Lymphocytes; Immunotherapy
PubMed: 37656775
DOI: 10.1126/sciimmunol.adg3868 -
Stem Cell Reports Apr 2023The thymus is critical for the establishment of a functional and self-tolerant adaptive immune system but involutes with age, resulting in reduced naive T cell output....
The thymus is critical for the establishment of a functional and self-tolerant adaptive immune system but involutes with age, resulting in reduced naive T cell output. Generation of a functional human thymus from human pluripotent stem cells (hPSCs) is an attractive regenerative strategy. Direct differentiation of thymic epithelial progenitors (TEPs) from hPSCs has been demonstrated in vitro, but functional thymic epithelial cells (TECs) only form months after transplantation of TEPs in vivo. We show the generation of TECs in vitro in isogenic stem cell-derived thymic organoids (sTOs) consisting of TEPs, hematopoietic progenitor cells, and mesenchymal cells, differentiated from the same hPSC line. sTOs support T cell development, express key markers of negative selection, including the autoimmune regulator (AIRE) protein, and facilitate regulatory T cell development. sTOs provide the basis for functional patient-specific thymic organoid models, allowing for the study of human thymus function, T cell development, and transplant immunity.
Topics: Humans; Thymus Gland; T-Lymphocytes; Pluripotent Stem Cells; Epithelial Cells; Cell Differentiation; Organoids
PubMed: 36963390
DOI: 10.1016/j.stemcr.2023.02.013 -
Frontiers in Immunology 2022For mechanistic studies, human B-cell differentiation and generation of plasma cells are invaluable techniques. However, the heterogeneity of both T-cell-dependent (TD)...
BACKGROUND/METHODS
For mechanistic studies, human B-cell differentiation and generation of plasma cells are invaluable techniques. However, the heterogeneity of both T-cell-dependent (TD) and T-cell-independent (TI) stimuli and the disparity of culture conditions used in existing protocols make the interpretation of results challenging. The aim of the present study was to achieve the most optimal B-cell differentiation conditions using isolated CD19 B cells and peripheral blood mononuclear cell (PBMC) cultures. We addressed multiple seeding densities, different durations of culturing, and various combinations of TD and TI stimuli including B-cell receptor (BCR) triggering. B-cell expansion, proliferation, and differentiation were analyzed after 6 and 9 days by measuring B-cell proliferation and expansion, plasmablast and plasma cell formation, and immunoglobulin (Ig) secretion. In addition, these conditions were extrapolated using cryopreserved cells and differentiation potential was compared.
RESULTS
This study demonstrates improved differentiation efficiency after 9 days of culturing for both B-cells and PBMC cultures using CD40L and IL-21 as TD stimuli and 6 days for CpG and IL-2 as TI stimuli. We arrived at optimized protocols requiring 2,500 and 25,000 B-cells per culture well for the TD and TI assays, respectively. The results of the PBMC cultures were highly comparable to the B-cell cultures, which allows dismissal of additional B-cell isolation steps prior to culturing. In these optimized TD conditions, the addition of anti-BCR showed a little effect on phenotypic B-cell differentiation; however, it interferes with Ig secretion measurements. The addition of IL-4 to the TD stimuli showed significantly lower Ig secretion. The addition of BAFF to optimized TI conditions showed enhanced B-cell differentiation and Ig secretion in B-cell but not in PBMC cultures. With this approach, efficient B-cell differentiation and Ig secretion were accomplished when starting from fresh or cryopreserved samples.
CONCLUSION
Our methodology demonstrates optimized TD and TI stimulation protocols for more in-depth analysis of B-cell differentiation in primary human B-cell and PBMC cultures while requiring low amounts of B cells, making them ideally suited for future clinical and research studies on B-cell differentiation of patient samples from different cohorts of B-cell-mediated diseases.
Topics: B-Lymphocytes; Cell Differentiation; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; T-Lymphocytes
PubMed: 35844625
DOI: 10.3389/fimmu.2022.815449 -
Clinical & Developmental Immunology 2012
Topics: Animals; Cell Differentiation; Humans; Infections; Lymphocytes
PubMed: 23251218
DOI: 10.1155/2012/510603 -
International Journal of Molecular... Jun 2023Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types... (Review)
Review
Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types (multi-lineage differentiation) over their lifetime. HSCs are mainly distributed in the bone marrow during adult life, harboring HSC populations and a hierarchy of different kinds of cells contributing to the "niche" that supports HSC regulation, myelopoiesis, and lymphopoiesis. In addition, HSC-like progenitors, innate immune cell precursors such as macrophages, mast cells, natural killer cells, innate lymphoid cells, and megakaryocytes and erythrocyte progenitor cells are connected by a series of complex ontogenic relationships. The first source of mast cells is the extraembryonic yolk sac, on embryonic day 7. Mast cell progenitors circulate and enter peripheral tissues where they complete their differentiation. Embryonic mast cell populations are gradually replaced by definitive stem cell-derived progenitor cells. Thereafter, mast cells originate from the bone marrow, developing from the hematopoietic stem cells via multipotent progenitors, common myeloid progenitors, and granulocyte/monocyte progenitors. In this review article, we summarize the knowledge on mast cell sources, particularly focusing on the complex and multifaceted mechanisms intervening between the hematopoietic process and the development of mast cells.
Topics: Mast Cells; Immunity, Innate; Lymphocytes; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Cell Lineage
PubMed: 37445862
DOI: 10.3390/ijms241310679 -
Critical Reviews in Immunology 2020T lymphocytes undergo carefully orchestrated programming during development in the thymus and subsequently during differentiation in the periphery. This intricate... (Review)
Review
T lymphocytes undergo carefully orchestrated programming during development in the thymus and subsequently during differentiation in the periphery. This intricate specification allows for cell-type and context-specific transcriptional programs that regulate immune responses to infection and malignancy. Epigenetic changes, including histone modifications and covalent modification of DNA itself through DNA methylation, are now recognized to play a critical role in these cell-fate decisions. DNA methylation is mediated primarily by the actions of the DNA methyltransferase (DNMT) and ten-eleven-translocation (TET) families of epigenetic enzymes. In this review, we discuss the role of DNA methylation and its enzymatic regulators in directing the development and differentiation of CD4+ and CD8+ T-cells.
Topics: Animals; Biomarkers; Cell Differentiation; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Humans; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 32749092
DOI: 10.1615/CritRevImmunol.2020033728 -
Frontiers in Immunology 2022The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic... (Review)
Review
The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic strategies. B cell-derived plasma cells are major players in inflammatory (auto)immune responses and can exhibit pro- or anti-inflammatory effects through (auto)antibody-dependent and -independent functions. Emerging evidence indicates a key role of nutrients and microbial metabolites in regulating the differentiation of plasma cells as well as their differentiation to pro- or anti-inflammatory phenotypes. These effects might be mediated indirectly by influencing other immune cells or directly through B cell-intrinsic mechanisms. Here, we provide an overview of nutrients and metabolites that influence B cell-intrinsic signaling pathways regulating B cell activation, plasma cell differentiation, and effector functions. Furthermore, we outline important inflammatory plasma cell phenotypes whose differentiation could be targeted by nutrients and microbial metabolites. Finally, we discuss possible implications for inflammatory (auto)immune conditions.
Topics: Plasma Cells; Autoimmunity; Cell Differentiation; B-Lymphocytes; Nutrients
PubMed: 36466846
DOI: 10.3389/fimmu.2022.1004644