STAT5 pathway: target of anti-CD4 antibody in attenuation of IL-2 receptor signaling.
BACKGROUND
Anti-CD4 antibodies induce long-term graft survival by incompletely understood mechanisms, and CD4-ligation with HIV gp120-derivatives attenuates interleukin (IL)-2 receptor signaling. We examined the latter in the context of the CD4-modulating antibody 16H5.


METHODS
We performed immunoblots to assess the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT)5 and Akt in the presence or absence of 16H5. Furthermore, we documented the effects of 16H5 on the induction of STAT5, activating protein (AP)-1, and myc by IL-2 in DNA-binding assays. 3H-thymidine incorporation of the human lymphoid cell line CMO, which exhibits constitutive activation of the STAT5 pathway and IL2-independent growth, was also measured during 16H5 treatment.


RESULTS
In human T lymphocytes, 16H5 attenuated both the tyrosine phosphorylation of STAT5 by IL-2 and the IL-2-induced DNA-binding of this transcription factor. In contrast, 16H5 had no effect on the serine phosphorylation of Akt by IL-2 or on the IL-2-induced DNA-binding of myc. Signal transduction involving AP-1 was unaffected by 16H5 and IL-2. 16H5 also attenuated CMO cell proliferation.


CONCLUSIONS
16H5 targets the STAT5 signaling pathway to attenuate IL-2 receptor signal transduction in human T cells. This observation provides a molecular explanation for the immunomodulatory actions of anti-CD4 antibodies.
Goebel
J
J
Department of Pediatrics, University of Kentucky Medical Center, Lexington 40536-0284, USA.
Forrest
K J
KJ
Mikovits
J
J
Emmrich
F
F
Volk
H D
HD
Lowry
R P
RP
D000906:Antibodies / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008894:Milk Proteins; D015375:Receptors, Interleukin-2 / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*
D000906:Antibodies; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators