TY - JOUR
T1 - Targeted Cleavage of Signaling Proteins by Caspase 3 Inhibits T Cell Receptor Signaling in Anergic T Cells
AU - Puga, Irene
AU - Rao, Anjana
AU - Macian, Fernando
N1 - Funding Information:
We thank members of our laboratories for helpful discussions and A.M. Cuervo and L. Santambrogio for critical reading of the manuscript. We thank T.W. Mak for the Casp3 −/− mice and S. Bathia for the CHO-IA d and CHO-IA d -B7 cell lines. We also thank C.J. McGlade for the GADS constructs and X.R. Bustelo for the Vav-1 expression plasmid. Human IL-2 and antibodies against murine IL-4 were obtained from the Biological Resources Branch preclinical repository. This work was supported by National Institutes of Health grants AI48213 (A.R.) and AI059738 (F.M.) and by the Irene Diamond Foundation (F.M.).
PY - 2008/8/15
Y1 - 2008/8/15
N2 - T cell receptor (TCR) engagement in the absence of costimulation induces the calcium-dependent upregulation of a program of gene expression that leads to the establishment of T cell anergy. Casp3 is one of the genes activated during anergy induction. Here we show that caspase 3 is required for the induction of T cell unresponsiveness. Suboptimal T cell stimulation induced caspase 3 activation, which did not result in cell death. Furthermore, caspase 3-deficient T cells showed impaired responses to anergizing stimuli. In anergic T cells, activated caspase 3 associated to the plasma membrane, where it cleaved and inactivated proteins such as the Grb2-related adaptor downstream of shc (GADS) and the guanine-nucleotide exchange factor Vav1, causing a blockade in TCR signaling. Our results identify a role for caspase 3 in nonapoptotic T cells and support that caspase 3-dependent proteolytic inactivation of signaling proteins is essential to maintain T cell tolerance.
AB - T cell receptor (TCR) engagement in the absence of costimulation induces the calcium-dependent upregulation of a program of gene expression that leads to the establishment of T cell anergy. Casp3 is one of the genes activated during anergy induction. Here we show that caspase 3 is required for the induction of T cell unresponsiveness. Suboptimal T cell stimulation induced caspase 3 activation, which did not result in cell death. Furthermore, caspase 3-deficient T cells showed impaired responses to anergizing stimuli. In anergic T cells, activated caspase 3 associated to the plasma membrane, where it cleaved and inactivated proteins such as the Grb2-related adaptor downstream of shc (GADS) and the guanine-nucleotide exchange factor Vav1, causing a blockade in TCR signaling. Our results identify a role for caspase 3 in nonapoptotic T cells and support that caspase 3-dependent proteolytic inactivation of signaling proteins is essential to maintain T cell tolerance.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=48749086577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48749086577&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2008.06.010
DO - 10.1016/j.immuni.2008.06.010
M3 - Article
C2 - 18701083
AN - SCOPUS:48749086577
SN - 1074-7613
VL - 29
SP - 193
EP - 204
JO - Immunity
JF - Immunity
IS - 2
ER -