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-Cbl Pathway
Mediate T Cell Hyporesponsiveness in Autoimmune
Nonobese Diabetic Mice
By
From the * Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario,
Canada N6G 2V4; and Nonobese diabetic (NOD) mouse thymocytes are hyporesponsive to T cell antigen receptor
(TCR)-mediated stimulation of proliferation, and this T cell hyporesponsiveness may be causal
to the onset of autoimmune diabetes in NOD mice. We previously showed that TCR-induced
NOD T cell hyporesponsiveness is associated with a block in Ras activation and defective signaling along the PKC/Ras/MAPK pathway. Here, we report that several sequential changes in
TCR-proximal signaling events may mediate this block in Ras activation. We demonstrate
that NOD T cell hyporesponsiveness is associated with the (a) enhanced TCR- Department of Microbiology and Immunology, University of Western
Ontario, London, Ontario, Canada N6G 2V4
-associated
Fyn kinase activity and the differential activation of the Fyn-TCR-
-Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-; (b) relative inability of the murine son of sevenless (mSOS) Ras GDP releasing factor activity to translocate
from the cytoplasm to the plasma membrane; and (c) exclusion of mSOS and PLC-
1 from the
TCR--associated Grb2/pp36-38/ZAP70 signaling complex. Our data suggest that altered tyrosine phosphorylation and targeting of the Grb2/pp36-38/ZAP70 complex to the plasma
membrane and cytoskeleton and the deficient association of mSOS with this Grb2-containing complex may block the downstream activation of Ras and Ras-mediated amplification of
TCR/CD3-mediated signals in hyporesponsive NOD T cells. These findings implicate mSOS
as an important mediator of downregulation of Ras signaling in hyporesponsive NOD T cells.
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