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Cellular signaling in thymocyte apoptosis
D J McConkey1, M Jondal, S Orrenius
1Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115.
Abstract:
Induction of apoptosis (programmed cell death) in response to T cell receptor triggering is now thought to be involved in the process of negative selection in the thymus, and current work is therefore aimed at investigating how apoptosis is regulated within the cells. To this end, recent work has implicated several of the well-known signal transduction pathways already known to regulate T cell activation in the regulation of apoptosis in thymocytes. In particular, elevations of the cytosolic Ca2+ level or increases in cAMP can trigger thymocyte apoptosis, whereas activation of protein kinase C appears to inhibit apoptosis in response to either induction pathway. Moreover, crosslinking of Thy-1, CD4, or CD8 leads to potentiation of T cell receptor-mediated cell death, effects that appear to involve protein tyrosine kinase activation. These observations may be relevant to the question of how T cell receptor occupancy can mediate both differentiation and death during intrathymic T cell development.
Insights
T cell receptor triggering induces apoptosis (programmed cell death) in thymocytes. Signal transduction pathways like calcium, cAMP, and protein kinase C regulate this cell death during T cell development.
Area of Science:
- Immunology
- Cell Biology
- Developmental Biology
Background:
- Apoptosis, or programmed cell death, is crucial for T cell development in the thymus.
- T cell receptor (TCR) triggering is implicated in negative selection, a process involving cell death.
Purpose of the Study:
- To investigate the regulatory mechanisms of apoptosis in thymocytes upon TCR triggering.
- To understand how signal transduction pathways influence TCR-mediated cell death in T cells.
Main Methods:
- Examining the role of cytosolic Ca2+ levels and cAMP in thymocyte apoptosis.
- Investigating the effects of protein kinase C (PKC) activation on apoptosis.
- Analyzing the impact of co-stimulatory molecule crosslinking (Thy-1, CD4, CD8) on TCR-mediated cell death.
- Assessing the involvement of protein tyrosine kinases in these processes.
Main Results:
- Elevated cytosolic Ca2+ and increased cAMP levels can trigger thymocyte apoptosis.
- Protein kinase C activation appears to inhibit apoptosis induced by Ca2+ or cAMP.
- Crosslinking of Thy-1, CD4, or CD8 potentiates TCR-mediated cell death, involving protein tyrosine kinases.
Conclusions:
- Signal transduction pathways significantly regulate apoptosis during thymocyte development.
- TCR occupancy can mediate both T cell differentiation and programmed cell death.
- Understanding these pathways is key to comprehending intrathymic T cell development.