| Guy Werlen, Ph.D., Associate Professor B333 Nelson Labs 604 Allison Road Piscataway, NJ 08854-6999 VOICE: (732) 445-8084 FAX: (732) 445-1794 werlen@biology.rutgers.edu |
Research Summary
T lymphocytes are key regulatory cells of the immune system. Their absence or malfunction can lead to severe immunodeficiency with the dramatic consequences that have been highlighted in the recent AIDS epidemic. On the other hand, T lymphocytes overreacting to self-ligands can result in 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.
T lymphocyte activation occurs upon binding of antigenic ligands to the T cell receptor (TCR), a receptor that is specifically expressed on the surface of those cells. Although functional 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 from which only ~3% will survive (positive selection), differentiate into functional T lymphocytes and migrate to the peripheral homing organs. Negative selection on the other hand, removes overtly self-reactive thymocytes from the repertoire. Thymic selection is thus critical for keeping an immunotolerant environment, where peripheral lymphocytes would only recognize foreign, but not self-ligands. Since both positive as well as negative selections require the specific binding of a ligand to the TCR, a central question in T cell biology is how does this receptor distinguish between survival and death signals. The work done in my laboratory aims at understanding the signal transduction mechanisms that control cell fate decisions of developing thymocytes, as well as activation and homeostasis of peripheral T lymphocytes.
Timing is everything
We have previously discovered that a fine-tuned balance between the activation kinetics of distinct signaling pathways may confer specificity to survival or death signals during thymic selection. For example, a slow but sustained activation of ERK, which peaks after JNK and p38 activation leads to positive selection and thymocyte survival, while a fast and transient ERK activation that peaks before JNK and p38 triggering leads to negative selection and cell death. Furthermore, a partially functional TCR which blocks positive but not negative selection totally abrogates the slow and sustained ERK activation, while the kinetics of JNK and p38 triggering are unaffected. This suggests that TCR engagement controls distinctly the kinetics of each MAPK cascade. We would like to understand the molecular mechanisms by which the TCR modulates the kinetics of specific signal transduction cascades that would lead to cell survival or death.
Since the cytosolic tail of the TCR lacks functionally relevant signaling domains, it interacts with various intracellular regulatory molecules by forming TCR-associated signaling complexes (TCR-signalosomes). It is therefore tempting to hypothesis that the formation of distinct TCR-signalosomes likely represents a mechanism by which the TCR achieves signaling specificity. A "positive selection signalosome" would activate a specific pathway transducing a survival signal, whereas a "negative selection signalosome" would bring about cell death signal transduction. By using transgenic mice models in combination with biochemical, genomic and proteomic approaches we will assess whether distinct TCR signalosomes act as molecular clocks in timely recruiting distinct signaling components that are specifically linked to survival or death modules as well as the particular gene expression programs that are induced respectively. Unraveling how distinct TCR-signalosomes modulate the duration of a preferential signaling cascade would eventually lead to the understanding of how the TCR can achieve signal specificity in distinguishing self- from non-self, a phenomenon that has fascinated immunologists for over 50 years.