Abstracts (complete list) - Wissenschaft Online

Dirk Brenner, Alexander Golks, Mareike Becker, Christian R. Frey, Rostislav Novak,
Friedemann Kiefer, Peter H. Krammer, Rüdiger Arnold
Regulation of Activation-induced Cell Death by T Cell
Receptor-Proximal Signalling
Lymphocyte homeostasis is strictly controlled to maintain physiological levels.
Activation-induced cell death (AICD) is one mechanism to delete superfluous and
autoreactive lymphocytes by restimulation of their immunoreceptors. So far
Immunoreceptor-proximal mechanisms leading to AICD are elusive. Here we
characterize Hematopoietic Progenitor Kinase 1 (HPK1) as a differentially regulated TCRproximal
signalling protein involved in AICD of primary T cells.
We show that HPK1 is a functional component of the endogenous I-κB kinase (IKK)
complex and prove HPK1 to be essential for TCR-mediated IKK and NF-κB activation.
We demonstrate proteolytic processing of HPK1 into HPK1-C specifically in AICDsensitive
primary T cells. The cleavage product HPK1-C sequesters the inactive IKK
complex and suppresses NF-κB upon TCR restimulation. T cells of HPK1-C transgenic
mice are sensitized towards TCR-mediated AICD. While it is well established that AICD
of T cells partially depends on the CD95/CD95L system we show T and B lymphocytes
from HPK1-C transgenic mice undergo AICD independently of CD95/CD95L. We show
that CD95L-dependent and HPK1/HPK1-C-mediated cell death pathways complement
each other in AICD of primary human T cells. Our results define HPK1 as a novel
regulator of AICD in lymphocytes.