CD28 co-stimulation restores T cell responsiveness in NOD mice by overcoming deficiencies in Rac-1/p38 mitogen-activated protein kinase signaling andIL-2 and IL-4 gene transcription

Previously, we reported that T cell hyporesponsiveness induced by TCR ligat ion is causal to autoimmune diabetes in NOD mice. Neonatal CD28 cc-stimulat ion reverses T cell hyporesponsiveness and protects NOD mice from diabetes by an IL-4-mediated mechanism, indicating that a deficiency in TCR signalin g may be overcome by CD28/B7-2 co-stimulation in NOD T cells. To investigat e which co-stimulation-induced signaling events mediate this protection, we analyzed the activity of Pas, Rac-1, mitogen-activated protein kinases (MA PK) and several transcription factors in TCR-activated NOD T cells in the p resence or absence of CD28 costimulation. We show that CD28 co-stimulation restores normal TOP-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 signal ing leading to the activation of AP-1 and NF-AT during IL-2 and IL-4 gene t ranscription. Our findings provide additional evidence that CD28 costimulat ion amplifies signals delivered by the TCR and further explain the mechanis m by which CD28 co-stimulation may protect against autoimmune diabetes.