Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system - PubMed (original) (raw)

Comparative Study

. 2002 Nov 26;99(24):15620-5.

doi: 10.1073/pnas.232565399. Epub 2002 Nov 12.

Affiliations

Comparative Study

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

Jonathan Kipnis et al. Proc Natl Acad Sci U S A. 2002.

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 BALBc 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 wild-type BALBc 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.

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Figures

Fig 1.

Fig 1.

Neonatal tolerance to myelin antigens abolishes spontaneous neuroprotection after optic nerve crush injury and spinal cord contusion. One-day-old SPD rats were tolerized to myelin antigens by i.p. injection, with 400 μg of WSCH emulsified in IFA. As adults, the rats were subjected to two kinds of CNS injury: (A) Partial crush injury of the optic nerve: the numbers of surviving neurons were significantly lower in the rats tolerized to myelin antigens than in control rats that were tolerized 1 day after birth with ovalbumin (OVA) or were not tolerized (P < 0.01 and P < 0.001, respectively). The figure shows the results of a representative experiment, one of two independent experiments (in each experiment n = 6–8 rats in each group). (B) Contusive injury of the spinal cord at the level of T9. Recovery was assessed by the locomotor activity score. The locomotor scores of myelin-tolerized contused rats were significantly lower than those of OVA-tolerized rats (n = 5 rats in each group; P < 0.01; two-tailed Student's t test).

Fig 2.

Fig 2.

Nonresponsiveness to CNS injury in rats neonatally immunized with spinal cord homogenate. Three days after being subjected to CNS injury the spleens were removed from rats and verified for T cell activation by using CD25 as an activation marker (ergotope)-α-chain of IL-2 receptor. CNS injury triggered activation of T cells in naïve rats and rats immunized at birth with nonmyelin proteins (Ova-tolerized), whereas activation of T cells was not observed in rats neonatally immunized with myelin proteins (WSCH-tolerized). The results are the mean of three experiments (n = 3 in each group in each experiment; P < 0.001).

Fig 3.

Fig 3.

Immunization of rats with WSCH improves neuronal survival after optic nerve crush injury. Four days before optic nerve injury, Lewis rats were immunized in the hind footpads with 3 mg of WSCH emulsified in CFA supplemented with 5 mg/ml Mycobacterium tuberculosis H37Ra. Retrograde labeling of the RGCs showed that significantly more neurons survived in rats immunized with WSCH than in PBS-injected rats. The results shown are of one representative experiment of three independent experiments (in each experiment, n = 7–8 in each group; P < 0.001, two-tailed Student's t test).

Fig 4.

Fig 4.

Thymectomy followed by split-dose irradiation in rats improves neuronal survival. Lewis (A) and SPD (B) rats (4 weeks old) were thymectomized (ThyX) and then subjected to split-dose irradiation (four bursts of 250 rad each at 2-week intervals). Immediately after the last irradiation the rats were subjected to partial optic nerve crush injury. Neuronal survival was determined 2 weeks later by application of a fluorescent dye. Significantly more neurons survived in the irradiated thymectomized Lewis rats (A) than in rats subjected to injury only. The results shown are of one representative experiment of three independent experiments (in each experiment, n = 7 in each group; P < 0.001, two-tailed Student's t test). (B) Significantly more neurons survived in the irradiated thymectomized SPD rats than in SPD rats subjected to injury only (n = 9 in each group; P < 0.01, two-tailed Student's t test).

Fig 5.

Fig 5.

Depletion of naturally occurring regulatory CD4+CD25+ T cells in BALB/c mice improves neuronal survival after optic nerve crush injury. (A) BALB/c mice were thymectomized (ThyX) 3 days after birth to deplete their regulatory T cells and were subjected as adults to severe unilateral crush injury inflicted on the intraorbital portion of the optic nerve. Surviving neurons were labeled by the application, 3 days before injury, of the neurotracer dye FluoroGold. Significantly more neurons survived in the thymectomized mice than in control (nonthymectomized) age-matched mice (n = 7–8 in each group; P < 0.001; Student's t test). (B) Neuronal survival after optic nerve crush injury in BALB/c nu/nu mice (devoid of T cells) was worse than in wild-type mice of matched background. Endogenous neuroprotection in the nude mice was restored by injection of 5 × 107 wild-type splenocytes. Injection of splenocytes depleted of regulatory CD4+CD25+ T cells increased neuronal survival in these mice beyond even that seen in the wild type (n = 5–6 in each group; P values between different groups, obtained by two-tailed Student's t test, are indicated by asterisks above the graph bars; *, P < 0.05; **, P < 0.01; ***, P < 0.001).

Fig 6.

Fig 6.

Naturally occurring regulatory CD4+CD25+ T cells diminish spontaneous neuroprotection_._ BALB/c mice, endowed with the spontaneous ability to evoke a protective beneficial autoimmune response, were injected with 2 × 106 purified activated regulatory CD4+CD25+ T cells. Control mice were injected with 2 × 106 purified activated effector cells (CD4+CD25−) or with PBS. Injection of regulatory T cells had an adverse effect on neuronal survival (more neurons underwent secondary degeneration). The results shown are of one representative experiment of three independent experiments; n = 5–6 mice in each group (P < 0.01 and 0.05; respectively).

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