Impaired Plasma Membrane Targeting of Grb2–Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn–T Cell Receptor (TCR)-ζ–Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice

Abstract

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-β–associated Fyn kinase activity and the differential activation of the Fyn–TCR-ζ–Cbl pathway, which may account for the impaired recruitment of ZAP70 to membrane-bound TCR-ζ; (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-γ1 from the TCR-ζ–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.

Displacement of Linker for Activation of T Cells from the Plasma Membrane Due to Redox Balance Alterations Results in Hyporesponsiveness of Synovial Fluid T Lymphocytes in Rheumatoid Arthritis

“…A similar observation has been described for autoimmune nonobese diabetic mice, where it was shown that a decrease in the phosphorylation of a 36-kDa protein upon TCR engagement in hyporesponsive T lymphocytes correlates with a decreased membrane targeting of PLC␥1 and the Grb2/Sos complex, and an impaired activation of Ras (40,41). The current data indicate that in SF T lymphocytes from RA patients this phosphoprotein represents the membrane-anchored 36-kDa adaptor protein LAT.…”

Low CD86 Expression in the Nonobese Diabetic Mouse Results in the Impairment of Both T Cell Activation and CTLA-4 Up-Regulation

“…In addition to the low CD86 expression in the NOD mouse described here, Delovitch and coworkers (15,16) have shown that signal transduction by the TCR-CD3 complex is defective in NOD, since the recruitment of Grb2, mSos, and PLC-␥1 to the cell membrane and activation of p21 ras upon TCR cross-linking are all diminished in NOD thymocytes. Therefore, the defective T cell proliferation and CTLA-4 up-regulation observed in NOD mice might be a consequence of the low CD86 levels in combination with the defective TCR-CD3 signaling previously reported.…”

Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

“…T cells from diabetic NOD mice and nondiabetic NOD mice at 18 wk of age are more susceptible to anti-CD3 (mitogenic and nonmitogenic)-induced AICD than T cells from 12-and 15-wk-old NOD mice. This may arise due to defective TCR signal transduction (41,42) that leads to decreased susceptibility to TCR-mediated activation and AICD in T cells from prediabetic NOD mice at 12 and 15 wk of age. These defects in NOD T cell signaling may also explain why a higher dose of anti-CD3 was required for the activation of NOD T cells than B6 T cells (43).…”