International Immunology, Vol. 13, No. 3, 377-384,
March 2001
© 2001 Japanese Society for Immunology
CD28 co-stimulation restores T cell responsiveness in NOD mice by overcoming deficiencies in Rac-1/p38 mitogen-activated protein kinase signaling and IL-2 and IL-4 gene transcription
1 Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario N6G 2V4, Canada
2 Departments of Microbiology and Immunology, and
3 Medicine, University of Western Ontario, London, Ontario N6A 5C1, Canada
Correspondence to: T. L. Delovitch, Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada
Previously, we reported that T cell hyporesponsiveness induced by TCR ligation is causal to autoimmune diabetes in NOD mice. Neonatal CD28 co-stimulation reverses T cell hyporesponsiveness and protects NOD mice from diabetes by an IL-4-mediated mechanism, indicating that a deficiency in TCR signaling may be overcome by CD28/B7-2 co-stimulation in NOD T cells. To investigate which co-stimulation-induced signaling events mediate this protection, we analyzed the activity of Ras, Rac-1, mitogen-activated protein kinases (MAPK) and several transcription factors in TCR-activated NOD T cells in the presence or absence of CD28 co-stimulation. We show that CD28 co-stimulation restores normal TCR-induced activation of Rac-1 and p38 MAPK in NOD T cells. Deficiencies in TCR-induced nuclear expression of activating protein (AP)-1 binding proteins as well as activation of AP-1 and NF-AT in the IL-2 and IL-4 P1 promoters are also corrected by CD28 co-stimulation. Thus, CD28 co-stimulation reverses NOD T cell hyporesponsiveness by restoring TCR signaling leading to the activation of AP-1 and NF-AT during IL-2 and IL-4 gene transcription. Our findings provide additional evidence that CD28 co-stimulation amplifies signals delivered by the TCR and further explain the mechanism by which CD28 co-stimulation may protect against autoimmune diabetes.
Keywords: NOD mice, signal transduction, T cell hyporesponsiveness
4 Present address: Department of Orthopedic Surgery, Rush-Presbyterian-St Luke's Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612, USA
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