Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 13
Targeting of the IFNgammaR2 dileucine-based (LI276-277) internalization motif
reinstates T cell sensitivity to the IFNgamma/STAT1-dependent apoptosis in vitro and
in vivo
Daniela Boselli1,2, Josiane Ragimbeau4, Paola Bernabei1, Roberto Chiarle1,3, Sandra
Pellegrini4, Mirella Giovarelli1,2, and Francesco Novelli1,2
1Center for Experimental Research and Medical Studies (CeRMS), San Giovanni
Battista Hospital, Via Santena 5, 10126 Turin, Italy; 2Department of Medicine and
Experimental Oncology, 3Department of Pathology, University of Turin, 10126 Turin,
Italy; 4Unit of Cytokine Signaling, Institut Pasteur, 75724 Paris, France
E-mail: daniela.boselli@unito.it
Activation of the IFNgamma (IFNg)/STAT1 pathway switches on many pro-apoptotic and
anti-proliferative genes. The downregulation of the IFNg receptor 2 chain (IFNgR2) has been
described in T lymphocytes and is thought to prevent activation of the apoptotic pathway. We
have previously shown that in human T lymphocytes IFNgR2 is internalized in a clathrindependent
manner and that this internalization is ligand-independent. Here we show that, in
Jurkat T cells, an IFNgR2 mutant in which the LI267-277 motif had been substituted with two
alanines (LI276-277AA) accumulated at the cell surface. The defective internalization of the
LI267-277AA mutant determined a strong and sustained IFNg-dependent response in terms of
STAT1 activation, IRF-1 and MHC class I induction, Fas and FasL cell surface up-regulation
and apoptosis. All these functions were weakly or not induced by IFNg in Jurkat cells
expressing wild type IFNgR2. The growth into SCID mice of ST4 malignant T cells
expressing the LI276-277AA mutant receptor, but not that of cells expressing the wild type
receptor, was inhibited by IFNg. These data indicate that the LI276-277 motif critically
controls ligand-independent internalization of IFNgR2 in T cells. This internalization motif
may provide a valuable therapeutic target for the reinstatement of IFNg/STAT1 apoptotic
signaling in autoreactive or neoplastic T cells.
- 346 -