Autoimmune CD4(+) T cells can mediate the ability to withstand neurodegenerative conditions. Here we show that the ability to spontaneously manifest a T cell-dependent protective response is restricted by naturally occurring CD4(+)CD25(+) regulatory T cells (Treg); depletion of Treg was beneficial in two mouse strains (C57BL/6J and BALB/c/OLA) differing in their spontaneous T cell-dependent ability to withstand the consequences of optic nerve injury. Passive transfer of exogenous Treg was destructive in BALB/c/OLA mice (which can spontaneously manifest a T cell-dependent protective anti-self response to injury) but beneficial in C57BL/6J mice (which have only limited ability to manifest such a response). This dichotomy was resolved by the finding that, in severe combined immunodeficient mice, a beneficial effect is obtained by passive transfer of either Treg-free CD4(+) T cells (Teff) or Treg alone, indicating that neuroprotection can be achieved by either Treg or Teff in the absence of the other. We attribute these disparate effects of Treg to their differential interaction (in part via IL-10 and transforming growth factor beta) with local innate immune cells (microglia) in the presence and in the absence of effector T cells. Activation of microglia by pro- and antiinflammatory cytokines in suitably controlled amounts might trigger different signal transduction pathways, each of which induces a neuroprotective microglial phenotype. These results suggest that, under neurodegenerative conditions, the effects of Treg, and possibly also of other regulatory T cells, might not be uniform, and that their expression in different individuals might be genetically determined. Therefore, therapeutic intervention based on induction of regulatory T cells might have limitations.