Dataset Information

Bcl6-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.

ABSTRACT: The transcriptional repressor Bcl6 has been reported as required for development of a subset of classical dendritic cell (cDCs) called cDC1, which is responsible for cross-presentation. However, mechanisms and in vivo functional analysis have been lacking. We generated a system for conditional deletion of Bcl6 in mouse cDCs. We confirmed the reported in vitro requirement for Bcl6 in cDC1 development and the general role for Bcl6 in cDC development in competitive settings. However, deletion of Bcl6 did not abrogate the in vivo development of cDC1. Instead, Bcl6 deficiency caused only a selective reduction in CD8α expression by cDC1 without affecting XCR1 or CD24 expression. Normal cDC1 development was confirmed in Bcl6^cKO mice by development of XCR1⁺ Zbtb46-GFP⁺ cDC1 by rejection of syngeneic tumors and by priming of tumor-specific CD8 T cells. In summary, Bcl6 regulates a subset of cDC1-specific markers and is required in vitro but not in vivo for cDC1 development.

SUBMITTER: Bagadia P

PROVIDER: S-EPMC8797952 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Bcl6-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.

Bagadia Prachi P O'Connor Kevin W KW Wu Renee R Ferris Stephen T ST Ward Jeffrey P JP Schreiber Robert D RD Murphy Theresa L TL Murphy Kenneth M KM

Journal of immunology (Baltimore, Md. : 1950) 20210616 1

The transcriptional repressor Bcl6 has been reported as required for development of a subset of classical dendritic cell (cDCs) called cDC1, which is responsible for cross-presentation. However, mechanisms and in vivo functional analysis have been lacking. We generated a system for conditional deletion of Bcl6 in mouse cDCs. We confirmed the reported in vitro requirement for Bcl6 in cDC1 development and the general role for Bcl6 in cDC development in competitive setti ...[more]

PMID: 34135058

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Project description:Acute and chronic rejection continue to represent serious challenges in transplant medicine. Current medical regimens focus on suppressing T-cell responses, lack effectiveness for some patients and impose significant risks of infection and malignancy. Recent studies have suggested that inhibition of co-stimulation pathways between antigen presenting cells (dendritic cells, macrophages, B-cells) and T-cells may serve as an effective strategy to prevent rejection by promoting allograft tolerance as opposed to simply suppressing immune responses. This concept has garnered excitement across the transplant community and demonstrated promising results in human renal transplant studies. A commonly used approach is inhibition of B7-CD28 and CD40-CD40L costimulatory pathways. Blocking these pathways leads to prolonged allograft survival in fully HLA-mismatched mouse heart transplantation models and non-human primates. There are important gaps in knowledge pertaining to mechanisms by which co-stimulation blockade modulates the recipient immune responses and confers donor organ tolerance. The precise immune cell populations and mechanisms responsible for induction and maintenance of donor organ tolerance remain incompletely understood. We have leveraged single cell RNA sequencing to dissect how traditional immunosuppression (cyclosporine) and co-stimulation blockade (CTLA-4 Ig, anti-CD40L neutralizing antibodies) differentially impact the immune landscape of the transplanted heart using a fully HLA-mismatched mouse model (Balb/c donor heart à B6 recipient). Analysis of these datasets demonstrated striking differences between these treatment regimens. Mice that received co-stimulation blockade displayed a marked increase in the abundance of classical dendritic cells (cDC1s and cDC2s). Compared to the cyclosporine treated group, these cells expressed negative regulators of T-cell stimulation including PDL1. Using recipient mice that lack either cDC1s or cDC2s, we found that cDC1s are absolutely required for co-stimulation blockade to confer long-term allograft survival and prevent recipient immune responses against the transplanted donor heart.

Project description:Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental malformation and frequent cause of drug-resistant focal epilepsy. We extend the findings, investigating the potential role of complement components C1q and C3 in synaptic pruning imbalance. Data from Type II FCD were compared with those obtained in focal epilepsies with different etiologies. Neocortical tissues were collected from 20 subjects, mainly adults with a mean age at surgery of 31 years, admitted to epilepsy surgery with a neuropathological diagnosis of: cryptogenic, temporal lobe epilepsy with hippocampal sclerosis, and Type IIa/b FCD. Dendritic spine density quantitation, evaluated in a previous paper using Golgi impregnation, was available in a subgroup. Immunohistochemistry, in situ hybridization, electron microscopy, and organotypic cultures were utilized to study complement/microglial activation patterns. FCD Type II samples presenting dendritic spine loss were characterized by an activation of the classical complement pathway and microglial reactivity. In the same samples, a close relationship between microglial cells and dendritic segments/synapses was found. These features were consistently observed in Type IIb FCD and in 1 of 3 Type IIa cases. In other patient groups and in perilesional areas outside the dysplasia, not presenting spine loss, these features were not observed. In vitro treatment with complement proteins of organotypic slices of cortical tissue with no sign of FCD induced a reduction in dendritic spine density. These data suggest that dysregulation of the complement system plays a role in microglia-mediated spine loss. This mechanism, known to be involved in the removal of redundant synapses during development, is likely reactivated in Type II FCD, particularly in Type IIb; local treatment with anticomplement drugs could in principle modify the course of disease in these patients.

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Bcl6-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.

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<i>Bcl6</i>-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.

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Bcl6-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.

Publications

&lt;i&gt;Bcl6&lt;/i&gt;-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.

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OmicsDI is part of the ELIXIR infrastructure

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<i>Bcl6</i>-Independent In Vivo Development of Functional Type 1 Classical Dendritic Cells Supporting Tumor Rejection.