TY - JOUR
T1 - Disengaging the IL-2 receptor with daclizumab enhances IL-7-mediated proliferation of CD4+ and CD8+ T Cells
AU - Monti, P.
AU - Brigatti, C.
AU - Heninger, A. K.
AU - Scirpoli, M.
AU - Bonifacio, E.
PY - 2009/12
Y1 - 2009/12
N2 - Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4 + and CD8+ T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T-cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies.
AB - Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4 + and CD8+ T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T-cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies.
KW - Immunosuppression
KW - T cell
KW - Transplant
KW - Zenapax
UR - http://www.scopus.com/inward/record.url?scp=72449208029&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=72449208029&partnerID=8YFLogxK
U2 - 10.1111/j.1600-6143.2009.02825.x
DO - 10.1111/j.1600-6143.2009.02825.x
M3 - Article
C2 - 19788505
AN - SCOPUS:72449208029
VL - 9
SP - 2727
EP - 2735
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 12
ER -