Abstracts (complete list) - Wissenschaft Online

Michael Probst-Kepper, Andrea Kroeger, Robert Geffers, Christian Erck, Miguel
Godinho, Vitor Martins dos Santos, Hansjörg Hauser, Jan Buer, Rudi Balling, Siegfried
Weiss
POSITIVE FEEDBACK-CONTROL BETWEEN GARP AND FOXP3
IN REGULATORY T CELLS
CD4 + CD25 hi regulatory T cells (Treg) have emerged as a unique population of
suppressor T cells that critically depend on the transcription factor FOXP3 for their
development and function. Therefore, FOXP3-transduction was suggested to generate
antigen-specific Treg cells. However, this approach is insufficient for human effector CD4
+ T cells (Th). Most likely this is due to the inadequate induction of the Treg-specific
receptor GARP (glycoprotein-A repetitions predominant). We identified GARP as master
switch receptor for Treg cells, since retroviral over-expression of GARP in antigenspecific
Th cells was sufficient to induce sustained high levels of FOXP3, regulatory
function, and an extended Treg/FOXP3-signature. Conversely, down-regulation of GARP
in Treg cells by short-interfering RNA reduced FOXP3 expression and suppressor
functions and vice versa, down-regulation of FOXP3 reduced GARP expression and
suppressor functions. Thus, a positive feedback-loop was established. Two minor
constituents of this regulatory circuit were identified, the endopeptidase legumain and
the β-galactoside binding protein LGALS3. Both up-regulated FOXP3 although not
reaching the levels induced by GARP. Whereas casein-kinase I phosphorylation at
position-6 of LGALS3 was essential for FOXP3 induction, the kruppel-like factor 2
(KLF2), involved in the regulation of T cell quiescence, was induced independent of this
phosphorylation. A preliminary computational model based on a hybrid functional Petri
net was developed to describe the main regulatory interactions. Thus, GARP represents
a promising tool for stable conversion of antigen-specific Th towards regulatory T cells,
the characterization of the underling regulatory network will be pivotal for an
understanding of the regulatory program.