| Guy Werlen
Associate Professor
Rutgers University
Cell Biology & Neuroscience
Nelson Laboratories - Busch Campus
Room B333
Piscataway. NJ 08855-1059
(732) 445-8084
FAX - 5870
werlen@biology.rutgers.edu |
Signaling networks & mechanisms that
control life and death of developing T lymphocytes
T lymphocytes are key regulatory cells of the
immune system. Their absence or malfunction can lead to severe immunodeficiency. as highlighted in the recent AIDS epidemic. as well as to autoimmune diseases
such as multiple sclerosis or juvenile diabetes. A fine-tuned orchestration of T
lymphocyte development and activation is therefore required for a fully
functional immune system that would only eliminate foreign but not self-ligands.
While T cells respond to infectious attacks in the periphery. they are generated
in the thymus from developing thymocytes. During their maturation. thymocytes
undergo a selection process whereby they either differentiate into functional T
lymphocytes (positive selection) or die (negative selection). ensuring an
immunotolerant environment. Since both forms of thymic selection require the
specific binding of a ligand to the T cell receptor (TCR). a central question in
T cell biology is how this receptor distinguishes signals leading to very
contradictory responses. such as cell differentiation and death.
Timing is everything
We have previously discovered that a fine-tuned balance between the activation
kinetics of distinct signaling pathways may confer specificity to positive or
negative selection. For example. a slow but sustained activation of ERK. which
peaks after JNK and p38 triggering leads to positive selection and thymocyte
survival. while a fast and transient ERK activation that peaks before JNK and
p38 brings about cell death.
As TCR-engagement also induces the recruitment of various proximal signaling
components to the receptor. it is tempting to hypothesis that the formation of
particular TCR-associated signaling complexes (TCR-signalosomes) might represent
a mechanism by which the TCR achieves signaling specificity. By using transgenic
mice models. as well as cultured cell lines in combination with various
molecular. biochemical. genomic and proteomic approaches. we would like to
assess whether distinct TCR signalosomes act as molecular clocks in timely
triggering specific signaling pathways and gene expression programs that would
lead to cell survival or death. Understanding the logic of TCR-signaling will
not only shed light on how T lymphocytes distinguish self- from non-self. a
phenomenon that has fascinated immunologists for over 50 years. but also
eventually explain how receptor-triggered signaling modules or pathways. specifically control survival or death in numerous cell systems.
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