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. Materials and Methods. We performed immunoblots to assess the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT)S and Akt in the presence or absence of 16H5. Furthermore, we documented the effects of 16H5 on the induction of STATE, activating protein (AP)-1, and myc by IL-2 in DNA-binding assays. H-3-thymidine incorporation of the human lymphoid cell line CMO, which exhibits constitutive activation of the STAT5 pathway and IL 2-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-I 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.

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