Spatial-temporal mapping of the T cell receptor NF-kappaB /
Title of Dissertation:
Spatial-Temporal Mapping of the T Cell Receptor NF-!B Signaling Pathway
Jeremy Shai Rossman, Doctor of Philosophy, 2005
Thesis Directed by:
Brian C. Schaefer, Ph.D.
Assistant Professor, Department of Microbiology and Immunology
T lymphocytes are critical mediators of adaptive immunity that recognize antigen
through the T cell receptor (TCR). Stimulation of the TCR leads to a complex signal
transduction cascade resulting in the activation of the transcription factors NFAT, AP-1
and NF-!B. The activation of these transcription factors is a crucial step in T lymphocyte
activation, allowing for proliferation and gain of effector function. TCR stimulation
results in the spatial redistribution of several proteins involved in signal transduction to
NF-!B. We find that the signaling intermediate Bcl10 forms cytoplasmic oligomers,
called POLKADOTS, upon antigen stimulation. The formation of these structures
requires the interaction between Bcl10 and MALT1 and is correlated with the activation
of NF-!B. Our research shows that POLKADOTS are foci for functional interactions
between signaling intermediates in TCR-mediated activation of NF-!B.
In addition to forming POLKADOTS in the cytoplasm in response to antigen
signals, a significant portion of cellular Bcl10 localizes to the nucleus in the steady state.
Observations of high enrichment of Bcl10 in the nucleus of MALT lymphoma tumor
cells suggest that Bcl10 nuclear localization may be actively regulated by signaling
processes. Aberrant redistribution of Bcl10 to the nucleus in MALT lymphomas may
contribute to tumorigenesis or pathogenesis. We show that Bcl10 is found in the nucleus
of T lymphocytes, that this localization is regulated by PKC", and that dose-dependent
interactions with MALT1 mediate the nuclear export of Bcl10. We also show that the N-
terminus of Bcl10 is essential for NF-!B activation, possibly by functioning as a
transcriptional enhancer for NF-!B-responsive genes. These results may further suggest
a pathogenic role for nuclear localization of Bcl10 in MALT lymphomas.
In summary, through spatial-temporal analysis of Bcl10 subcellular localization and
protein-protein interactions, we have further elucidated the role played by Bcl10 in health
and in disease.
School:Uniformed Services University of the Health Sciences
School Location:USA - Maryland
Source Type:Master's Thesis
Keywords:receptors antigen t cell nf kappa b lymphocytes signal transduction adaptor proteins neoplasm caspases
Date of Publication:01/01/2006