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Nature Oct 2022Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary...
Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (T) cell development. Within weeks of birth, a separate wave of T cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota, yet the cell types responsible for the generation of peripheral T (pT) cells have not been identified. Here we describe the identification of a class of RORγt antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I-TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pT cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pT generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pT differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pT generation, further implicating TC IV as the tolerogenic RORγt antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.
Topics: Cell Differentiation; Dendritic Cells; Epithelial Cells; Gastrointestinal Microbiome; Immunity, Innate; Nuclear Receptor Subfamily 1, Group F, Member 3; Thymus Gland; Transforming Growth Factor beta; Antigen-Presenting Cells; T-Lymphocytes, Regulatory; Immune Tolerance; Lymph Nodes
PubMed: 36070798
DOI: 10.1038/s41586-022-05309-5 -
The Journal of Experimental Medicine Jan 2021Dendritic cells (DCs) contribute a small fraction of the tumor microenvironment but are emerging as an essential antitumor component based on their ability to foster T... (Review)
Review
Dendritic cells (DCs) contribute a small fraction of the tumor microenvironment but are emerging as an essential antitumor component based on their ability to foster T cell immunity and immunotherapy responses. Here, we discuss our expanding view of DC heterogeneity in human tumors, as revealed with meta-analysis of single-cell transcriptome profiling studies. We further examine tumor-infiltrating DC states that are conserved across patients, cancer types, and species and consider the fundamental and clinical relevance of these findings. Finally, we provide an outlook on research opportunities to further explore mechanisms governing tumor-infiltrating DC behavior and functions.
Topics: Dendritic Cells; Gene Expression Profiling; Humans; Neoplasms; Tumor Microenvironment
PubMed: 33601412
DOI: 10.1084/jem.20200264 -
Nature Communications Jun 2022Immunogenic cell death significantly contributes to the success of anti-cancer therapies, but immunogenicity of different cell death modalities widely varies....
Immunogenic cell death significantly contributes to the success of anti-cancer therapies, but immunogenicity of different cell death modalities widely varies. Ferroptosis, a form of cell death that is characterized by iron accumulation and lipid peroxidation, has not yet been fully evaluated from this perspective. Here we present an inducible model of ferroptosis, distinguishing three phases in the process-'initial' associated with lipid peroxidation, 'intermediate' correlated with ATP release and 'terminal' recognized by HMGB1 release and loss of plasma membrane integrity-that serves as tool to study immune cell responses to ferroptotic cancer cells. Co-culturing ferroptotic cancer cells with dendritic cells (DC), reveals that 'initial' ferroptotic cells decrease maturation of DC, are poorly engulfed, and dampen antigen cross-presentation. DC loaded with ferroptotic, in contrast to necroptotic, cancer cells fail to protect against tumor growth. Adding ferroptotic cancer cells to immunogenic apoptotic cells dramatically reduces their prophylactic vaccination potential. Our study thus shows that ferroptosis negatively impacts antigen presenting cells and hence the adaptive immune response, which might hinder therapeutic applications of ferroptosis induction.
Topics: Cell Death; Dendritic Cells; Ferroptosis; Humans; Lipid Peroxidation; Neoplasms
PubMed: 35760796
DOI: 10.1038/s41467-022-31218-2 -
Trends in Immunology Jan 2021Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs can also acquire tolerogenic... (Review)
Review
Dendritic cells (DCs), the most efficient antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs can also acquire tolerogenic functions in vivo and in vitro in response to various stimuli, including interleukin (IL)-10, transforming growth factor (TGF)-β, vitamin D3, corticosteroids, and rapamycin. In this review, we provide a wide perspective on the regulatory mechanisms, including crosstalk with other cell types, downstream signaling pathways, transcription factors, and epigenetics, underlying the acquisition of tolerogenesis by DCs, with a special focus on human studies. Finally, we present clinical assays targeting, or based on, tolerogenic DCs in inflammatory diseases. Our discussion provides a useful resource for better understanding the biology of tolerogenic DCs and their manipulation to improve the immunological fitness of patients with certain inflammatory conditions.
Topics: Autoimmunity; Dendritic Cells; Humans; Immune Tolerance; Inflammation; Signal Transduction; T-Lymphocytes
PubMed: 33293219
DOI: 10.1016/j.it.2020.11.001 -
Life Sciences Aug 2020Dendritic cells (DCs) are considered as professional antigen presenting cells (APCs), containing a variety of subsets, that can be resident in organs or migrating among... (Review)
Review
Dendritic cells (DCs) are considered as professional antigen presenting cells (APCs), containing a variety of subsets, that can be resident in organs or migrating among the lymphoid and non-lymphoid organs. In a normal steady condition, DCs concomitantly process and present antigens on major histocompatibility complex (MHC) class I and II. However, they are further activated after exposing to antigens. Recently, several approaches have been exerted to improve antigen presentation potency, to elicit powerful immune responses against tumor cells. In DC-based cancer immunotherapy, DC is obtained from patient and modulated ex vivo in order to entice the immune system toward tumor elimination. Several approaches have been on the evaluation for long-term anti-tumor immune responses by DCs. On the other side, combination of DC vaccines with other cancer therapies, like chemotherapy and monoclonal antibodies could confer efficient cancer therapeutics. In this review article, we first go through the immunobiology of DC, and development of DC vaccines. Then, we concentrate on the DC immunotherapy by highlighting combinational approaches to enhance the efficacy of cancer treatment strategies.
Topics: Adjuvants, Immunologic; Antigen Presentation; Combined Modality Therapy; Dendritic Cells; Humans; Immunotherapy; Neoplasms; Radiotherapy; Tumor Microenvironment
PubMed: 32205087
DOI: 10.1016/j.lfs.2020.117580 -
International Journal of Molecular... Feb 2023Dendritic cells (DCs) are acknowledged as the most potent professional antigen-presenting cells (APCs), able to induce adaptive immunity and support the innate immune...
Dendritic cells (DCs) are acknowledged as the most potent professional antigen-presenting cells (APCs), able to induce adaptive immunity and support the innate immune response [...].
Topics: Humans; Dendritic Cells; Adaptive Immunity; Immunity, Innate; Neoplasms
PubMed: 36835665
DOI: 10.3390/ijms24044253 -
International Journal of Molecular... Jan 2023We have implemented an improved, cost-effective, and highly reproducible protocol for a simple and rapid differentiation of the human leukemia monocytic cell line THP-1...
We have implemented an improved, cost-effective, and highly reproducible protocol for a simple and rapid differentiation of the human leukemia monocytic cell line THP-1 into surrogates for immature dendritic cells (iDCs) or mature dendritic cells (mDCs). The successful differentiation of THP-1 cells into iDCs was determined by high numbers of cells expressing the DC activation markers CD54 (88%) and CD86 (61%), and the absence of the maturation marker CD83. The THP-1-derived mDCs are characterized by high numbers of cells expressing CD54 (99%), CD86 (73%), and the phagocytosis marker CD11b (49%) and, in contrast to THP-1-derived iDCs, CD83 (35%) and the migration marker CXCR4 (70%). Treatment of iDCs with sensitizers, such as NiSO and DNCB, led to high expression of CD54 (97%/98%; GMFI, 3.0/3.2-fold induction) and CD86 (64%/96%; GMFI, 4.3/3.2-fold induction) compared to undifferentiated sensitizer-treated THP-1 (CD54, 98%/98%; CD86, 55%/96%). Thus, our iDCs are highly suitable for toxicological studies identifying potential sensitizing or inflammatory compounds. Furthermore, the expression of CD11b, CD83, and CXCR4 on our iDC and mDC surrogates could allow studies investigating the molecular mechanisms of dendritic cell maturation, phagocytosis, migration, and their use as therapeutic targets in various disorders, such as sensitization, inflammation, and cancer.
Topics: Humans; Cell Line; Dendritic Cells; Cell Differentiation
PubMed: 36674966
DOI: 10.3390/ijms24021452 -
Pathologie (Heidelberg, Germany) Aug 2022Histiocytic and dendritic cell neoplasms (HDCNs) represent very rare tumors, which have been the subject of debate during the last few years. (Review)
Review
BACKGROUND
Histiocytic and dendritic cell neoplasms (HDCNs) represent very rare tumors, which have been the subject of debate during the last few years.
OBJECTIVES
We aimed to provide a comprehensive review of the subject.
MATERIALS AND METHODS
The experience gained by the authors in large international studies and as a national reference center has been summarized to highlight the characteristics of each entity.
RESULTS
The clinical, morphologic, phenotypic, and molecular data of the different entities included under the heading of HDCNs are extensively discussed.
CONCLUSION
Currently, HDCNs are classified in the group of orphan diseases for which a standardized therapy is lacking. An international registry would facilitate expansion and dissemination of knowledge of these diseases and improve their treatment.
Topics: Dendritic Cells; Histiocytes; Neoplasms
PubMed: 36175665
DOI: 10.1007/s00292-022-01116-x -
Surgical Pathology Clinics Sep 2019Histiocytic and dendritic cell neoplasms are very rare, belonging to a group that share morphologic, immunophenotypic, and ultrastructural characteristics of mature... (Review)
Review
Histiocytic and dendritic cell neoplasms are very rare, belonging to a group that share morphologic, immunophenotypic, and ultrastructural characteristics of mature histiocytic/dendritic neoplasms. Histiocytic and dendritic cell neoplasms may arise de novo or in association with B-cell, T-cell, or myeloid neoplasms. Recent molecular findings, particularly the discoveries of the mutations in the RAS-RAF-MEK-ERK pathway, have greatly advanced the diagnosis and treatment options. Histiocytic and dendritic cell neoplasms may closely resemble each other, non-hematopoietic neoplasms, and even reactive processes. Therefore, it is essential to understand the clinicopathologic characteristics, differential diagnoses, and pitfalls of each entity.
Topics: Dendritic Cells; Diagnosis, Differential; Histiocytic Disorders, Malignant; Humans; Prognosis
PubMed: 31352989
DOI: 10.1016/j.path.2019.03.013 -
Hematology/oncology Clinics of North... Jun 2020
Topics: Dendritic Cells; Disease Management; Disease Susceptibility; Humans; Myeloproliferative Disorders
PubMed: 32336426
DOI: 10.1016/j.hoc.2020.02.011