Unique CD8+ T Cell Priming by Antigen Presenting Plasmacytoid Dendritic Cells Compared to Conventional Dendritic Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261447 | GEO | 2025/02/01
REPOSITORIES: GEO
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| GSE261447_230221_MR.featureCounts.s2.overlap.txt.gz | Txt |
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Project description:Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumors. Although this function is traditionally attributed to dendritic cells, tumor-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumor-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbor hyperactive cysteine protease activity in their lysosomes which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) targeted to lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases present specifically inside lysosomes of TAMs, improves their ability to cross-present antigens, and attenuates tumor growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumor regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.
2021-10-14 | PXD028037 | Pride
Project description:Functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses essential for host protection. We found that KDM5C, a histone lysine demethylase, regulates conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs, have increased proportions of cDC2Bs and cDC1s, which was partly dependent on type I interferon and pDCs. Loss of KDM5C resulted in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I interferon and can more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and reduced function. In response to Listeria infection, KDM5C-deficient mice mounted reduced CD8 responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and a critical driver functional properties of DCs.
2024-09-25 | GSE262866 | GEO
Project description:Functional and phenotypic heterogeneity of dendritic cells (DCs) plays a crucial role in facilitating the development of diverse immune responses essential for host protection. We found that KDM5C, a histone lysine demethylase, regulates conventional DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs, have increased proportions of cDC2Bs and cDC1s, which was partly dependent on type I interferon and pDCs. Loss of KDM5C resulted in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I interferon and can more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and reduced function. In response to Listeria infection, KDM5C-deficient mice mounted reduced CD8 responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and a critical driver functional properties of DCs.
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Project description:This a model from the article:
A dynamical perspective of CTL cross-priming and regulation: implications for
cancer immunology.
Wodarz D, Jansen VA. Immunol Lett
2003 May 1;86(3):213-27 12706524
,
Abstract:
Cytotoxic T lymphocytes (CTL) responses are required to fight many diseases such
as viral infections and tumors. At the same time, they can cause disease when
induced inappropriately. Which factors regulate CTL and decide whether they
should remain silent or react is open to debate. The phenomenon called
cross-priming has received attention in this respect. That is, CTL expansion
occurs if antigen is recognized on the surface of professional antigen
presenting cells (APCs). This is in contrast to direct presentation where
antigen is seen on the surface of the target cells (e.g. infected cells or tumor
cells). Here we introduce a mathematical model, which takes the phenomenon of
cross-priming into account. We propose a new mechanism of regulation which is
implicit in the dynamics of the CTL: According to the model, the ability of a
CTL response to become established depends on the ratio of cross-presentation to
direct presentation of the antigen. If this ratio is relatively high, CTL
responses are likely to become established. If this ratio is relatively low,
tolerance is the likely outcome. The behavior of the model includes a parameter
region where the outcome depends on the initial conditions. We discuss our
results with respect to the idea of self/non-self discrimination and the danger
signal hypothesis. We apply the model to study the role of CTL in cancer
initiation, cancer evolution/progression, and therapeutic vaccination against
cancers.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Wodarz D, Jansen VA. (2003) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
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