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Apoptotic signaling in lymphocytes
C M Rudin1, J Van Dongen, C B Thompson
1Gwenn Knapp Center for Lupus and Immunology Research, University of Chicago, IL 60637-5420, USA.
Abstract:
Two families of cell surface receptors are integral to the control of lymphocyte survival and programmed cell death (apoptosis): the tumor necrosis factor receptor family and the CD28/CTLA4 family. Tumor necrosis factor receptor family members bind a related collection of ligands (the tumor necrosis factor family) that can either induce or inhibit cell death. Two of the tumor necrosis factor receptor family members, tumor necrosis factor receptor 1 and Fas, have been implicated in the termination of immune responses through their ability to induce apoptosis. A number of cytoplasmic proteins implicated in signal generation by these receptors recently have been identified. These proteins fall into several related classes sharing intriguing structural motifs. The CD28 and CTLA4 molecules share at least two extracellular ligands and signaling through the two receptors appears to determine the apoptotic sensitivity of activated T cells. The effects of CD28 and CTLA4 on cell survival are dependent on T-cell antigen receptor engagement, providing a potent mechanism for clonally specific T-cell expansion or deletion. The study of the apoptotic pathways in lymphocytes has led to a better understanding of the mechanisms of autoimmune disease and serves as a model system for the study of the regulation of cell survival and tissue homeostasis.
Insights
Lymphocyte survival and apoptosis are regulated by the tumor necrosis factor receptor and CD28/CTLA4 families. These cell surface receptors control immune responses and T-cell fate, impacting autoimmune disease understanding.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Cell surface receptors critically regulate lymphocyte survival and programmed cell death (apoptosis).
- Key families involved include the tumor necrosis factor receptor (TNFR) family and the CD28/CTLA4 family.
- TNFR family members bind tumor necrosis factor (TNF) ligands, influencing cell death induction or inhibition.
Purpose of the Study:
- To elucidate the roles of TNFR and CD28/CTLA4 families in lymphocyte apoptosis.
- To understand the signaling mechanisms and cytoplasmic proteins involved in receptor-mediated apoptosis.
- To explore how these pathways contribute to immune response termination and T-cell homeostasis.
Main Methods:
- Identification and characterization of cytoplasmic proteins involved in TNFR and CD28/CTLA4 signaling.
- Analysis of structural motifs in signaling proteins.
- Investigating the dependence of CD28/CTLA4 effects on T-cell antigen receptor engagement.
Main Results:
- Two TNFR members, TNFR1 and Fas, are implicated in immune response termination via apoptosis.
- Cytoplasmic proteins with shared structural motifs have been identified in signaling pathways.
- CD28 and CTLA4 signaling influences T-cell apoptotic sensitivity, dependent on T-cell antigen receptor engagement.
Conclusions:
- TNFR and CD28/CTLA4 signaling pathways are crucial for regulating T-cell survival and apoptosis.
- These pathways provide mechanisms for clonal T-cell expansion or deletion.
- Studying lymphocyte apoptosis offers insights into autoimmune disease and tissue homeostasis.