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Autocrine activation by interferon-gamma of STAT factors following T cell activation.

Research paper by J J Girdlestone, M M Wing

Indexed on: 01 Mar '96Published on: 01 Mar '96Published in: European Journal of Immunology



Abstract

The activation of T cells requires engagement of the T cell receptor/CD3 complex and co-stimulatory molecules, and results in the triggering of several signaling pathways which lead rapidly to the nuclear translocation of several transcription factors, such as nuclear factor (NF)-kappa B and NF-AT. A result of this activation process is the induction of a number of genes, including those encoding cytokines such as interleukin-2, tumor necrosis factor-alpha, and interferon (IFN)-gamma which have important immunoregulatory effects. We report here that a DNA-binding factor containing STAT1 also becomes activated in human peripheral blood T lymphocytes or Jurkat cells, although not until 1-2 h after stimulation. Activation is delayed a further 1-2 hr when mononuclear cell cultures are stimulated by an antigen which requires processing. Appearance of the STAT1 factor is significantly reduced in the presence of cyclosporin A, and blocked by cycloheximide, indicating that its activation is dependent upon a protein(s) synthesized in response to initial signaling events. Neutralizing antiserum against IFN-gamma, but not other cytokines tested, blocked activation of the factor almost completely, and IFN-gamma was found in the culture supernatants of stimulated cells at levels at which recombinant IFN-gamma could activate the factor in naive cells. Therefore, a STAT1 transcription factor is activated by IFN-gamma synthesized and released upon stimulation of T lymphocyte populations. While Jurkat cells both secrete and respond to IFN-gamma in an autocrine loop, it seems likely that the responding cells may differ from those synthesizing this cytokine in the mononuclear cell cultures in the light of the recent report that Th1 cells lack the IFN-gamma receptor chain necessary for activation of STAT1 (Pernis, A., Gupta, S., Gollob, K.J., Garfein, E., Coffman, R.L., Schindler, C., and Rothman, P., Science 1995. 269:245).