Conventional Type 1 Dendritic Cells in Intestinal Immune Homeostasis

Sasaki, Izumi; Kato, Takashi; Hemmi, Hiroaki; Fukuda‐Ohta, Yuri; Wakaki-Nishiyama, Naoko; Yamamoto, Asumi; Kaisho, Tsuneyasu

doi:10.3389/fimmu.2022.857954

Cited by 8 publications

(7 citation statements)

References 86 publications

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“…For pDCs, we employed CLEC4C (C-type lectin domain family 4 member C), and NRP1 (neuropilin 1) ( 59 – 61 ). For cDC1, we utilized CLEC9A (Dendritic cell C-type lectin receptor 9A), XCR1 (XC chemokine receptor 1), and THBD (thrombomodulin) ( 59 , 60 , 62 – 64 ). cDC2 was characterized using CLEC10A (C-type lectin domain containing 10A), and CD163 (CD163 molecule) ( 59 , 60 , 65 ).…”

Section: Resultsmentioning

confidence: 99%

A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery

et al. 2023

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Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique ability to mediate inflammatory responses of the immune system. Given the critical role of DCs in shaping immunity, they present an attractive avenue as a therapeutic target to program the immune system and reverse immune disease disorders. To ensure appropriate immune response, DCs utilize intricate and complex molecular and cellular interactions that converge into a seamless phenotype. Computational models open novel frontiers in research by integrating large-scale interaction to interrogate the influence of complex biological behavior across scales. The ability to model large biological networks will likely pave the way to understanding any complex system in more approachable ways. We developed a logical and predictive model of DC function that integrates the heterogeneity of DCs population, APC function, and cell-cell interaction, spanning molecular to population levels. Our logical model consists of 281 components that connect environmental stimuli with various layers of the cell compartments, including the plasma membrane, cytoplasm, and nucleus to represent the dynamic processes within and outside the DC, such as signaling pathways and cell-cell interactions. We also provided three sample use cases to apply the model in the context of studying cell dynamics and disease environments. First, we characterized the DC response to Sars-CoV-2 and influenza co-infection by in-silico experiments and analyzed the activity level of 107 molecules that play a role in this co-infection. The second example presents simulations to predict the crosstalk between DCs and T cells in a cancer microenvironment. Finally, for the third example, we used the Kyoto Encyclopedia of Genes and Genomes enrichment analysis against the model’s components to identify 45 diseases and 24 molecular pathways that the DC model can address. This study presents a resource to decode the complex dynamics underlying DC-derived APC communication and provides a platform for researchers to perform in-silico experiments on human DC for vaccine design, drug discovery, and immunotherapies.

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Section: Resultsmentioning

confidence: 99%

A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery

et al. 2023

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“…They polarize CD8 + T cells and are specialized in cross-presentation, a process in which exogenous antigens are processed and presented on MHCI molecules, and cDC1 are therefore important for self-tolerance in steady state. Furthermore, they play an essential role in the induction of tumor specific CD8 + cytotoxic T cells ( 2 ). cDC2 are more heterogeneous, with two main cDC2 populations existing in the intestine.…”

Section: Discussionmentioning

confidence: 99%

“…The tumor tissue represents an intricate system consisting not only of malignant cells, but also of surrounding stroma and, in particular, a complex tumor immune cell infiltrate. This includes cells of the innate immune system like dendritic cells (DC), macrophages (Mph), neutrophils, and myeloid-derived suppressor cells (MDSC), as well as adaptive immune cells (T and B cells) ( 1 , 2 ). These diverse cell types contribute to the inflammatory status of the tumor tissue and communicate with each other directly via cell-cell contact or indirectly through cytokine and chemokine production to shape tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Isolation and high-dimensional flow cytometric analysis of tumor-infiltrating leukocytes in a mouse model of colorectal cancer

Eich,

Vogt,

Längst

et al. 2024

Front. Immunol.

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Colorectal cancer (CRC) is a complex and heterogeneous disease characterized by dysregulated interactions between tumor cells and the immune system. The tumor microenvironment plays a pivotal role in cancer initiation as well as progression, with myeloid immune cells such as dendritic cell and macrophage subsets playing diverse roles in cancer immunity. On one hand, they exert anti-tumor effects, but they can also contribute to tumor growth. The AOM/DSS colitis-associated cancer mouse model has emerged as a valuable tool to investigate inflammation-driven CRC. To understand the role of different leukocyte populations in tumor development, the preparation of single cell suspensions from tumors has become standard procedure for many types of cancer in recent years. However, in the case of AOM/DSS-induced colorectal tumors, this is still challenging and rarely described. For one, to be able to properly distinguish tumor-associated immune cells, separate processing of cancerous and surrounding colon tissue is essential. In addition, cell yield, due to the low tumor mass, viability, as well as preservation of cell surface epitopes are important for successful flow cytometric profiling of tumor-infiltrating leukocytes. Here we present a fast, simple, and economical step-by-step protocol for isolating colorectal tumor-associated leukocytes from AOM/DSS-treated mice. Furthermore, we demonstrate the feasibility of this protocol for high-dimensional flow cytometric identification of the different tumor-infiltrating leukocyte populations, with a specific focus on myeloid cell subsets.

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“…For example, dendritic cells are classified into conventional dendritic cells (cDCs) and plasmacytoid dendritic cells, inflammatory dendritic cells and Langerhans cells ( 64 ). cDCs are further subclassified into cDC1 and cDC2 ( 65 ), each with a different phenotype and function. For example, cDC1 are efficient cross-presenters ( 65 , 66 ) while cDC2 cells can efficiently prime naïve CD4 + T cells ( 65 , 67 , 68 ).…”

Section: What Are the Factors That Shape The T Cell Response To A Par...mentioning

confidence: 99%

“…cDCs are further subclassified into cDC1 and cDC2 ( 65 ), each with a different phenotype and function. For example, cDC1 are efficient cross-presenters ( 65 , 66 ) while cDC2 cells can efficiently prime naïve CD4 + T cells ( 65 , 67 , 68 ). On the other side of the immunological synapse, T cells can exist in different states, for example, naïve, effector, memory, and anergic T cells, each of which have a different antigenic sensitivity ( 69 , 70 ), and even utilize different metabolic pathways ( 71 ).…”

Section: What Are the Factors That Shape The T Cell Response To A Par...mentioning

confidence: 99%

Challenges and opportunities in analyzing and modeling peptide presentation by HLA-II proteins

ElAbd¹,

Bächer

Tholey

et al. 2023

Front. Immunol.

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The human leukocyte antigen (HLA) proteins are an indispensable component of adaptive immunity because of their role in presenting self and foreign peptides to T cells. Further, many complex diseases are associated with genetic variation in the HLA region, implying an important role for specific HLA-presented peptides in the etiology of these diseases. Identifying the specific set of peptides presented by an individual’s HLA proteins in vivo, as a whole being referred to as the immunopeptidome, has therefore gathered increasing attention for different reasons. For example, identifying neoepitopes for cancer immunotherapy, vaccine development against infectious pathogens, or elucidating the role of HLA in autoimmunity. Despite the tremendous progress made during the last decade in these areas, several questions remain unanswered. In this perspective, we highlight five remaining key challenges in the analysis of peptide presentation and T cell immunogenicity and discuss potential solutions to these problems. We believe that addressing these questions would not only improve our understanding of disease etiology but will also have a direct translational impact in terms of engineering better vaccines and in developing more potent immunotherapies.

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Conventional Type 1 Dendritic Cells in Intestinal Immune Homeostasis

Cited by 8 publications

References 86 publications

A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery

A multiscale mechanistic model of human dendritic cells for in-silico investigation of immune responses and novel therapeutics discovery

Isolation and high-dimensional flow cytometric analysis of tumor-infiltrating leukocytes in a mouse model of colorectal cancer

Challenges and opportunities in analyzing and modeling peptide presentation by HLA-II proteins

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