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Blood, 1 February 2006, Vol. 107, No. 3, pp. 987-993.
Prepublished online as a Blood First Edition Paper on October 6, 2005; DOI 10.1182/blood-2005-07-2834.
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IMMUNOBIOLOGY
Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo
M. Pilar Gil,
Rachelle Salomon,
Jennifer Louten, and
Christine A. Biron
From the Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI.
Type 1 interferons (IFNs) are induced in vivo, administered therapeutically, and potential targets for amelioration of autoimmune diseases. The cytokines mediate profound antiproliferative effects. Signal transducer and activator of transcription 1 (STAT1)-dependent signaling pathways are required for inhibition of proliferation, and viral infections can elicit high levels of type 1 IFNs as well as total STAT1 protein expression. Thus, a mechanism must be in place to help antigen-specific T cells overcome IFN-induced inhibition of proliferation. The studies reported here demonstrate that total CD8 T-cell proliferation in the presence of IFNs, ex vivo in response to cytokines and in vivo during viral infection, is inhibited through a STAT1-dependent mechanism. In contrast, major proportions of antigen-specific CD8, but not CD4, T cells are rendered less sensitive to this inhibition, express lower endogenous levels of total STAT1, and are selectively proliferating in the presence of type 1 IFN, at key times after viral challenge. Taken together, these novel results show that differential STAT1 expression is used by the immune system to modify cytokine-mediated effects on T-cell expansion and have implications for the consequences of therapeutic intervention in cytokine function.
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