Biology subjects

Berkowitz, N.

Publications and source records attributed to Berkowitz, N..

4 recordsLinked to original sources

bioRxiv2026

Self-antigen disrupts cDC1 mediated antitumor responses

Conventional dendritic cells navigate complex tissues and sample peripheral antigens, balancing immune suppression and activation to achieve tissue homeostasis. However, it remains unclear how an individual dendritic cells reconciles co-incident signals from immunological opposing antigens within the tissue or tumor microenvironment, where tolerogenic self-antigen and immunogenic tumor antigen or microbes coexist. Here, using complementary in vivo fluorescent reporter systems, high-resolution imaging and endosomal profiling, we simultaneously tracked uptake, intracellular processing and cross-presentation of cutaneous self, tumor and microbial antigens in murine skin tissue, tumors and draining lymph nodes. We find that a substantial fraction of dendritic cells acquire antigen from multiple sources and that localization within endosomal compartments is dictated by antigen source. Notably, type 1 conventional dendritic cells that co-process self and tumor antigen represent a significant proportion of tumor antigen-bearing dendritic cells in the tumor and tumor draining lymph node. These dual-antigen loaded dendritic cells display a diminished capacity to prime tumor-specific CD8+ T cells and a marked reduction in tumor derived peptide presented on surface MHCI, while cross-priming of self-antigen specific T cells is significantly increased. These changes occur despite equivalent or greater tumor antigen uptake relative to self-antigen and high expression of surface MHCI and costimulatory molecules. Together, these data support a model in which multiantigen processing within dendritic cells can bias peptide loading away from tumor-derived epitopes, thereby limiting tumor-specific cross-priming. Modulating the antigenic context of the tumor microenvironment or endosomal routing after antigen uptake may therefore represent a strategy to restore effective dendritic cell-mediated antitumor immunity.

immunology↗

bioRxiv2025

Contextual control of CD8+ T cell priming by dendritic cell subsets in tumor and inflammatory microenvironments

Conventional dendritic cells orchestrate adaptive immunity by trafficking peripheral antigens to draining lymph nodes and presenting peptide-MHC complexes to prime naive T cells. Migratory and lymph node resident conventional dendritic cell subsets occupy distinct anatomical niches and have been shown to shape T cell activation in a variety of immunologic contexts including infection, vaccination and cancer. How peripheral tissue context and dendritic cell subset specific transcriptional programs collaborate to determine CD8+ T cell priming remains incompletely defined. Using fluorescent antigen, we tracked antigen distribution, dendritic cell transcriptional programming, and functional cross-presentation across tumor, inflammatory, and steady state tissue contexts. We find that skin tumor antigen is more widely distributed amongst draining lymph node conventional dendritic cells than skin antigen derived from either steady state or inflamed skin tissue. Comparing across dendritic cell subsets, migratory type 1 dendritic cells display higher expression of MHCI antigen presentation machinery and genes associated with cross-presentation compared with lymph node resident type 1 dendritic cells in tumor and inflamed tissue contexts. Similarly, they exhibited superior per-cell cross-presentation and stronger induction of naive CD8+ T cell responses. We find that both antigen access in the lymph node and context-specific cross-presentation efficiency together predict the magnitude and quality of CD8+ T cell priming. These results identify migratory dendritic cells, particularly type 1, as central mediators of antitumor CD8+ T cell responses and support therapeutic strategies that augment the efficiency of resident dendritic cell cross-presentation.

immunology↗

bioRxiv2024

Synchronous activation of striatal cholinergic interneurons induces local serotonin release

Striatal cholinergic interneurons (CINs) activate nicotinic acetylcholine receptors on dopamine axons to extend the range of dopamine release. Here we show that synchronous activation of CINs induces and extends the range of local serotonin release via a similar mechanism. This process is exaggerated in the hypercholinergic striatum of a mouse model of OCD-like behavior, implicating CINs as critical regulators of serotonin levels in the healthy and pathological striatum.

neuroscience↗

bioRxiv2021

Non-uniform distribution of dendritic nonlinearities differentially engages thalamostriatal and corticostriatal inputs onto cholinergic interneurons

The tonic activity of striatal cholinergic interneurons (CINs) is modified differentially by their afferent inputs. Although their unitary synaptic currents are identical, in most CINs cortical inputs onto distal dendrites only weakly entrain them, whereas proximal thalamic inputs trigger abrupt pauses in discharge in response to salient external stimuli. To test whether the dendritic expression of the active conductances that drive autonomous discharge contribute to the CINs capacity to dissociate cortical from thalamic inputs, we used an optogenetics-based method to quantify dendritic excitability. We found that the persistent sodium (NaP) current gave rise to dendritic boosting, and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) current gave rise to a subhertz membrane resonance. This resonance may underlie our novel finding of an association between CIN pauses and internally-generated slow wave events in sleeping non-human primates. Moreover, our method indicated that dendritic NaP and HCN currents were preferentially expressed in proximal dendrites. We validated the non-uniform distribution of NaP currents pharmacologically; with two-photon imaging of dendritic back-propagating action potentials; and by demonstrating boosting of thalamic, but not cortical, inputs by NaP currents. Thus, the localization of active dendritic conductances in CIN dendrites mirrors the spatial distribution of afferent terminals and may promote their differential responses to thalamic vs. cortical inputs.

neuroscience↗