PURPOSE. Protective autoimmunity attenuates secondary degeneration after central nervous system (CNS) injury. Such neuroprotection is achieved via activation of autoimmune CD4+CD25- effector T cells (Teffs) or suppression of naturally occurring CD4+CD25+ regulatory T cells (Tregs). In this study the ability of bacterial DNA, characterized by unmethylated CpG islands, to downregulate Treg activity and therefore, to confer neuroprotection was investigated. METHODS. The effects of CpG on suppressive activity of mouse Tregs were studied by coculturing Tregs with Teffs and measuring proliferation by radiolabeled thymidine. The neuroprotective effects of CpG-mediated Treg suppression was examined in rats after optic nerve crush. RESULTS. Teff proliferation in response to T-cell receptor stimuli was significantly reduced when the Teffs were cocultured with Tregs, compared with Teff activation when cultured alone. Treating Tregs with CpG reduced their suppressive activity and restored Teff proliferation to baseline levels. CpG injection in rats with optic nerve crush conferred significant neuroprotection compared with that in untreated control rats (118 ± 8 cells/mm2 vs. 69 ± 5 cells/mm2, respectively; mean ± SEM; P < 0.05). CpG-mediated neuroprotection was accompanied by significantly increased T-cell infiltration at the injury site. Similar CpG treatment of athymic nude rats yielded no neuroprotection, further suggesting a T-cell-dependent mechanism of CpG action. CONCLUSIONS. These findings strongly support the notion that alleviation of Treg suppression after injury benefits neuronal survival. Bacterial DNA attenuation of Treg suppressive activity may represent an evolutionary adaptation that curbs the amplified infection risk after CNS trauma, due to blood-brain barrier breakdown. This study may prompt development of new neuroprotective therapies aimed at the immune system, to benefit the injured CNS.