Dataset Information

Receptor editing constrains development of phosphatidyl choline-specific B cells in V_H12-transgenic mice.

ABSTRACT: B1 B cells reactive to phosphatidyl choline (PtC) exhibit restricted immunoglobulin heavy chain (HC) and light chain (LC) combinations, exemplified by V_H12/Vκ4/5H. Two checkpoints are thought to focus PtC⁺ B cell maturation in V_H12-transgenic mice (VH12 mice): V-J rearrangements encoding a "permissive" LC capable of V_H12 HC pairing are selected first, followed by positive selection based on PtC binding, often requiring LC receptor editing to salvage PtC^- B cells and acquire PtC reactivity. However, evidence obtained from breeding VH12 mice to editing-defective dnRAG1 mice and analyzing LC sequences from PtC⁺ and PtC^- B cell subsets instead suggests that receptor editing functions after initial positive selection to remove PtC⁺ B cells in VH12 mice. This offers a mechanism to constrain natural, polyreactive B cells to limit their frequency. Sequencing also reveals occasional in-frame hybrid LC genes, reminiscent of type 2 gene replacement, that, testing suggests, arise via a recombination-activating gene (RAG)-independent mechanism.

SUBMITTER: Worth AN

PROVIDER: S-EPMC9716649 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Receptor editing constrains development of phosphatidyl choline-specific B cells in VH12-transgenic mice.

Worth Alexandra N AN Palmer Victoria L VL Schabla N Max NM Perry Greg A GA Fraser-Philbin Anna N AN Swanson Patrick C PC

Cell reports 20220601 11

B1 B cells reactive to phosphatidyl choline (PtC) exhibit restricted immunoglobulin heavy chain (HC) and light chain (LC) combinations, exemplified by VH12/Vκ4/5H. Two checkpoints are thought to focus PtC+ B cell maturation in VH12-transgenic mice (VH12 mice): V-J rearrangements encoding a "permissive" LC capable of VH12 HC pairing are selected first, followed by positive selection based on PtC binding, often requiring LC receptor editing to salvage Pt ...[more]

PMID: 35705027

Similar Datasets

Project description:Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5'-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.

Dataset Information

Receptor editing constrains development of phosphatidyl choline-specific B cells in V_H12-transgenic mice.

Publications

Receptor editing constrains development of phosphatidyl choline-specific B cells in V<sub>H</sub>12-transgenic mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets