Biology subjects

Chudnovskiy, A.

Publications and source records attributed to Chudnovskiy, A..

4 recordsLinked to original sources

bioRxiv2024

Distinct components of nucleoside-modified messenger RNA vaccines cooperate to instruct efficient germinal center responses

Nucleoside-modified mRNA vaccines elicit protective antibodies through their ability to promote T follicular helper (Tfh) cells. The lipid nanoparticle (LNP) component of mRNA vaccines possesses inherent adjuvant activity. However, to what extent the nucleoside-modified mRNA can be sensed and contribute to Tfh cell responses remains largely undefined. Herein, we deconvoluted the signals induced by LNP and mRNA that instruct dendritic cells (DCs) to promote Tfh cell differentiation. We demonstrated that the nucleoside-modified mRNA drives the production of type I interferons that act on DCs to induce their maturation and the induction of Th1-biased Tfh responses. Conversely, LNP favors the acquisition of a Tfh cell-inducing program in DCs, a stronger Th2 polarization in Tfh cells, and allows for rapid mRNA translation by DCs within the draining lymph node. Our work unravels distinct adjuvant features of mRNA and LNP necessary for the induction of Tfh cells, with implications for vaccine design.

immunology↗

bioRxiv2023

Universal recording of cell-cell contacts in vivo for interaction-based transcriptomics

Cellular interactions are essential for tissue organization and functionality. In particular, immune cells rely on direct and usually transient interactions with other immune and non-immune populations to specify and regulate their function. To study these "kiss-and-run" interactions directly in vivo, we previously developed LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts), an approach that uses enzymatic transfer of a labeled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ helper T cells and antigen presenting cells, however. Here, we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the cellular partners of regulatory T cells in steady state, and identify germinal center (GC)-resident T follicular helper (Tfh) cells based on their ability to interact cognately with GC B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalog of the immune populations that physically interact with intestinal epithelial cells (IECs) and find evidence of stepwise acquisition of the ability to interact with IECs as CD4+ T cells adapt to residence in the intestinal tissue. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.

immunology↗

bioRxiv2022

Proximity-dependent labeling identifies dendritic cells that prime the antitumor CD4+ T cell response

Dendritic cells (DCs) are uniquely capable of transporting tumoral antigens to tumor-draining lymph nodes (tdLNs), and also interact with effector T cells within the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identify individual DCs capable of presenting antigen to CD4+ T cells in the tdLN as well as inside the tumor microenvironment (TME). Our findings reveal that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both within tumors and in the tdLN, and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation within the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.

immunology↗

bioRxiv2019

Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. Yet the specific immune dysregulations within the atherosclerotic lesions that lead to clinical cerebro- and cardiovascular complications (i.e. ischemic stroke and myocardial infarction) are poorly understood. Here, using single-cell mass cytometry with Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) we found that atherosclerotic plaques were enriched in activated, differentiated, and exhausted subsets of T cells vs. blood. Next, using single-cell proteomic, transcriptomic, and cell-to-cell interaction analyses we found unique functional dysregulations of both T cells and macrophages in plaques of patients with clinically symptomatic (SYM; recent stroke of TIA) or asymptomatic (ASYM, no recent stroke) carotid artery disease. SYM plaques were enriched with a distinct CD4+ T cell subset, and T cells were activated, differentiated and presented subset specific exhaustion. SYM macrophages presented alternatively activated phenotypes including subsets associated with plaque vulnerability. In ASYM plaques, T cells and macrophages were activated and displayed a strong IL-1{beta} signaling across cell types, that was absent in SYM plaques. The identification of plaque-specific innate and adaptive immune dysregulations associated with cerebrovascular events provides the basis for the design of precisely tailored cardiovascular immunotherapies.

immunology↗