Disengaging the IL-2 receptor with daclizumab enhances IL-7-mediated proliferation of CD4(+) and CD8(+) T cells.
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.
Immunology of Diabetes Unit and Clinical Transplant Unit, San Raffaele Scientific Institute, Milan, Italy.
P
P
Monti
C
C
Brigatti
A K
AK
Heninger
M
M
Scirpoli
E
E
Bonifacio
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000077561:Daclizumab; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000187:drug effects / Q000276:immunology*; D015851:Interleukin-7 / Q000502:physiology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis; D050799:STAT5 Transcription Factor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C507941:IL2RG protein, human; D007074:Immunoglobulin G; D053631:Interleukin Receptor Common gamma Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D000077561:Daclizumab