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*
Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, La Jolla, CA 92037;
Alliance Pharmaceutical Corporation, San Diego, CA 92121;
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and Department of Medicine, Harvard Medical School, Boston, MA 02115
The role of the STAT4 signaling pathway in autoimmune diabetes was
investigated using the rat insulin promoter lymphocytic
choriomeningitis virus model of virally induced autoimmune diabetes.
Abrogation of STAT4 signaling significantly reduced the development of
CD4+-T cell-dependent but not CD4+-T
cell-independent diabetes, illustrating the fine-tuned kinetics
involved in the pathogenesis of autoimmunity. However, the absence of
STAT4 did not prevent the generation of autoreactive Th1/Tc1 T cell
responses, as well as protective antiviral immunity. Protection from
insulin-dependent diabetes mellitus was associated with decreased
numbers of autoreactive CTL precursors in the pancreas and the spleen
and a general as well as Ag-specific reduction of IFN-
secretion by
T lymphocytes. A shift from Th1 to Th2 T cell immunity was not
observed. Hence, our results implicate both CTL and cytokines in ß
cell destruction. Selective inhibition of the STAT4 signal transduction
pathway might constitute a novel and attractive approach to prevent
clinical insulin-dependent diabetes mellitus in prediabetic individuals
at risk.
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