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.

Selected Publications

Clarke RL, Thiemann S, Refaeli Y, Werlen G, Potter TA. (2009) A new function for LAT and CD8 during CD8-mediated apoptosis that is independent of TCR signal transduction. Eur J Immunol. May 15. [Epub ahead of print]

Werlen G. (2008) Thymocyte-fate decisions: bittersweet new flavor. Blood. 112(1):7-8.

Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, Werlen G, Hollander GA, Gascoigne NR, Palmer E. (2006) Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature. 444(7120):724-9.

Lovatt M, Filby A, Parravicini V, Werlen G, Palmer E, Zamoyska R. (2006) Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response. Mol Cell Biol. 26(22):8655-65.

Werlen G. Hausmann B. Naeher D. Palmer E. (2003) Signaling life and death in the thymus: timing is everything. Science. 299(5614):1859-63. Review.

Werlen G. Palmer E. (2002) The T-cell receptor signalosome: a dynamic structure with expanding complexity. Curr Opin Immunol. 14(3):299-305. Review.

Rosette C. Werlen G. Daniels MA. Holman PO. Alam SM. Travers PJ. Gascoigne NR. Palmer E. Jameson SC. (2001) The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model. Immunity. 15(1):59-70.

Werlen G. Hausmann B. Palmer E. (2000) A motif in the alphabeta T-cell receptor controls positive selection by modulating ERK activity. Nature. 406(6794):422-6.