Dietary antigens influence the antigen presentation pathway of small intestine epithelium
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA487175 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7738230_1.fastq.gz | Fastqsanger.gz | |||
| SRR7738230_2.fastq.gz | Fastqsanger.gz | |||
| SRR7738231_1.fastq.gz | Fastqsanger.gz | |||
| SRR7738231_2.fastq.gz | Fastqsanger.gz | |||
| SRR7738232_1.fastq.gz | Fastqsanger.gz |
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Project description:Epithelial cells of the small intestine are designed to absorb the nutrients from the diet, so we tested if the absence of dietary macromolecules and protein antigens had an impact on the physiological condition of IECs. We generated RNAseq data from small intestine IECs isolated from mice free of any conventional non-self antigens for TCRab T cells. A comparison with RNAseq data generated from IECs isolated from SPF or GF mice showed clear differences between the transcriptomes of IECs isolated from the AF, SPF or GF mice.
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Project description:This model of the immune system response to antigen presentation is based on the publication:
Eduardo D.Sontag (2017) 'A Dynamic Model of Immune Responses to Antigen Presentation Predicts Different Regions of Tumor or Pathogen Elimination', Cell Systems, 4(2)
DOI: 10.1016/j.cels.2016.12.003
Comment:
This model is based on the "toy model" as described by Equations 1A-1C from the manuscript and the system represented by Equation 2, which exhibits a type of incoherent feedforward loop (IFFL).
Abstract:
The immune system must discriminate between agents of disease and an organism’s healthy cells. While the identification of an antigen as self/non-self is critically important, the dynamic features of antigen presentation may also determine the immune system’s response. Here, we use a simple mathematical model of immune activation to explore the idea of antigen discrimination through dynamics. We propose that antigen presentation is coupled to two nodes, one regulatory and one effecting the immune response, through an incoherent feedforward loop and repressive feedback. This circuit would allow the immune system to effectively estimate the increase of antigens with respect to time, a key determinant of immune reactivity in vivo. Our model makes the prediction that tumors growing at specific rates evade the immune system despite the continuous presence of antigens indicating disease, a phenomenon closely related to clinically observed “two-zone tolerance.” Finally, we discuss a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells.
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Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity.
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Project description:Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knock out mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.
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Project description:Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. It is currently unknown whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function. Here we show that human colorectal cancer (CRC)-derived CAFs display an enhanced capacity to cross-present neoantigen-derived synthetic long peptides (SLPs) when compared to normal colonic fibroblasts. Importantly, cross-presentation of antigens required the lysosomal protease Cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD25, CD137) and increased exhaustion (TIM3) marker expression. Our data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.
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