Neuroprotective autoimmunity: Naturally occurring CD4 ⁺ CD25 ⁺ regulatory T cells suppress the ability to withstand injury to the central nervous system

Abstract

The ability of rats or mice to withstand the consequences of injury to myelinated axons in the CNS was previously shown to depend on the ability to manifest a T cell-mediated protective immune response, which is amenable to boosting by myelin-specific T cells. Here we show that this ability, assessed by retinal ganglion cell survival after optic nerve injury or locomotor activity after spinal cord contusion, is decreased if the animals were immunized as neonates with myelin proteins (resulting in their nonresponsiveness as adults to myelin proteins) or injected with naturally occurring regulatory CD4 ؉ CD25 ؉ T cells immediately after the injury, and is improved by elimination of these regulatory T cells. In nude BALB͞c mice replenished with a splenocyte population lacking CD4 ؉ CD25 ؉ regulatory T cells, significantly more neurons survived after optic nerve injury than in nude mice replenished with a complete splenocyte population or in matched wild-type controls. In contrast, neuronal survival in wildtype BALB͞c mice injected with CD4 ؉ CD25 ؉ regulatory T cells immediately after injury was significantly worse than in noninjected controls. These findings suggest that the ability to cope with the sequelae of a CNS insult is affected unfavorably by nonresponsiveness to myelin self-antigens and favorably by conditions allowing rapid expression of an autoimmune response. The regulatory T cells might represent an evolutionary compromise between the need to avoid autoimmune diseases and the need for autoimmunity on alert for the purpose of tissue maintenance.

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

“…Relative to normal rodents, those deprived of mature T cells lose significantly more neurons after a CNS insult (13,15). Experimental evidence suggests that, under stress, the CNS signals to the immune system, evoking an adaptive immune response that is directed against abundant antigens residing at the site of the lesion (15,16,31,32). Individuals differ in their ability to spontaneously evoke such an immune response (13).…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…This latter cell type, in particular CD4 + T cells, are most relevant since it was recently shown that the key role of A 2A Rs in attenuating peripheral tissue damage from ischemiaYreperfusion injury is due to the activation of A 2A Rs in CD4 + T cells [322]. Since the depletion of CD4 + YCD25 + regulatory T cells has been shown to promote survival of neurons after brain insults [323], in a manner regulated by metabotropic receptors such as dopamine D 1 receptors [324], it would be interesting to test if A 2A Rs might affect this particular population of T cells to control brain injury. However, the urgent need remains to provide a logical explanation for the fundamentally opposite effects of A 2A Rs in cell death involving inflammatory reactions in the brain and in the periphery.…”

Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

“…Studies from our laboratory have shown that recovery from CNS injury is critically dependent on the well controlled activity of T cells directed to specific CNS autoantigens (5,6). These autoreactive T cells evidently regulate microglia in a way that renders them supportive of neuronal survival and neural tissue repair (7)(8)(9)(10).…”