Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival.
Julie Zikherman1, Kristin Doan, Ramya Parameswaran
1Division of Rheumatology, Department of Medicine, Rosalind Russell Medical Research Center for Arthritis and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Summary
The receptor-like tyrosine phosphatase CD45 positively regulates B-cell receptor signaling, impacting B-cell development and tolerance. High CD45 expression leads to altered B-cell populations and reduced survival signaling.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- CD45 (receptor-like tyrosine phosphatase) regulates Src family kinases in antigen receptor signaling.
- CD45 deficiency models are complicated by the redundant phosphatase CD148.
- Previous models obscure the precise roles of CD45 in B-cell development and tolerance.
Purpose of the Study:
- To elucidate the specific roles of CD45 in B-cell receptor (BCR) signaling and B-cell tolerance.
- To overcome limitations of CD45-deficient mouse models.
- To investigate the impact of titrated CD45 expression on B-cell development and autoreactivity.
Main Methods:
- Utilized an allelic series of mice with titrated CD45 expression (0-180%).
- Analyzed B-cell development, receptor editing, and tolerance in the IgHEL/sHEL model.
- Assessed B-cell activating factor receptor (BAFFR) expression and BAFF-induced survival.
Main Results:
- CD45 exclusively plays a positive regulatory role in BCR signaling, unlike its inhibitory role in T-cell receptor (TCR) signaling.
- Increased CD45 expression enhances BCR signaling, leading to increased receptor editing and loss of follicular and marginal zone B cells.
- High CD45 expression converts B-cell anergy into deletion and impairs BAFF-induced B-cell survival by reducing BAFFR expression.
Conclusions:
- CD45 function diverges significantly between T cells and B cells.
- High CD45 expression acts as a critical checkpoint for censoring autoreactive B cells during development.
- CD45 regulates B-cell survival through modulation of BAFFR expression and response to BAFF.
Related Concept Videos
01:22T Cell Activation and Clonal Selection
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
Naive T cells that have not yet encountered an antigen express two primary CD...
01:24B Cell Activation and Differentiation
The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...