Neonatal Activation of CD28 Signaling Overcomes T Cell Anergy and Prevents Autoimmune Diabetes by an IL-4–dependent Mechanism

Optimal T cell responsiveness requires signaling through the T cell receptor (TCR) and CD28 costimulatory recep-tors. Previously, we showed that T cells from autoimmune nonobese diabetic (NOD) mice display proliferative hypore-sponsiveness to TCR stimulation, which may be causal to the development of insulin-dependent diabetes mellitus (IDDM). Here, we demonstrate that anti-CD28 mAb stimulation re-stores complete NOD T cell proliferative responsiveness by augmentation of IL-4 production. Whereas neonatal treat-ment of NOD mice with anti-CD28 beginning at 2 wk of age inhibits destructive insulitis and protects against IDDM by enhancement of IL-4 production by islet-infiltrating T cells, administration of anti-CD28 beginning at 5–6 wk of age does not prevent IDDM. Simultaneous anti–IL-4 treatmen