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Apoptosis mediated by the TNF-related cytokine and receptor families
C F Ware1, S VanArsdale, T L VanArsdale
1Division of Biomedical Sciences, University of California, Riverside 92521, USA.
Abstract:
T lymphocytes use several specialized mechanisms to induce apoptotic cell death. The tumor necrosis factor (TNF)-related family of membrane-anchored and secreted ligands represent a major mechanism regulating cell death and cell survival. These ligands also coordinate differentiation of tissue to defend against intracellular pathogens and regulate development of lymphoid tissue. Cellular responses are initiated by a corresponding family of specific receptors that includes two distinct TNFR (TNFR60 and TNFR80), Fas (CD95), CD40, p75NTF, and the recently identified lymphotoxin beta-receptor (LT beta R), among others. The MHC-encoded cytokines, TNF and LT alpha, form homomeric trimers, whereas LT beta assembles into heterotrimers with LT alpha, creating multimeric ligands with distinct receptor specificities. The signal transduction cascade is initiated by transmembrane aggregation (clustering) of receptor cytoplasmic domains induced by binding to their multivalent ligands. The TRAF family of Zn RING/finger proteins bind to TNFR80; CD40 and LT beta R are involved in induction NF kappa B and cell survival. TNFR60 and Fas interact with several distinct cytosolic proteins sharing the "death domain" homology region. TNF binding to TNFR60 activates a serine protein kinase activity and phosphoproteins are recruited to the receptor forming a multicomponent signaling complex. Thus, TNFRs use diverse sets of signaling molecules to initiate and regulate cell death and survival pathways.
Insights
T lymphocytes utilize tumor necrosis factor (TNF)-related ligands and receptors to regulate cell death and survival. Diverse signaling pathways are initiated by ligand binding, influencing cellular responses and tissue development.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- T lymphocytes employ specialized mechanisms, including the tumor necrosis factor (TNF)-related family of ligands and receptors, to control apoptosis, cell survival, and immune responses.
- These ligands and their corresponding receptors, such as TNFR60, TNFR80, Fas, CD40, and lymphotoxin beta-receptor (LT beta R), are crucial for tissue differentiation and defense against pathogens.
- Ligand binding triggers receptor aggregation, initiating signal transduction cascades that dictate cellular fate.
Purpose of the Study:
- To elucidate the diverse mechanisms by which T lymphocytes regulate cell death and survival through TNF-related pathways.
- To detail the specific roles of various TNF receptor superfamily members and their associated signaling molecules.
- To understand how ligand-receptor interactions initiate distinct intracellular signaling cascades.
Main Methods:
- Analysis of TNF-related ligand and receptor families involved in T lymphocyte function.
- Investigation of receptor-ligand interactions, including multimeric ligand assembly (homotrimers and heterotrimers).
- Examination of signal transduction pathways initiated by receptor clustering, including TRAF proteins and death domain interactions.
Main Results:
- TNF-related ligands and receptors are central to regulating T cell-mediated apoptosis and survival.
- Specific receptors like TNFR80, CD40, and LT beta R engage TRAF proteins and NF kappa B pathways for cell survival.
- TNFR60 and Fas interact with death domain proteins, with TNF binding to TNFR60 activating kinase activity and forming signaling complexes.
Conclusions:
- T lymphocytes utilize a sophisticated array of TNF-related signaling molecules to control cell death and survival pathways.
- The diversity in receptor-ligand interactions and downstream signaling components allows for precise regulation of cellular responses.
- Understanding these pathways is critical for comprehending immune function, lymphoid tissue development, and responses to intracellular pathogens.