Immune Surveillance in the Injured Nervous System: T-Lymphocytes Invade the Axotomized Mouse Facial Motor Nucleus and Aggregate around Sites of Neuronal Degeneration

Abstract

Although the CNS is an established immune-privileged site, it is under surveillance by the immune system, particularly under pathological conditions. In the current study we examined the lymphocyte infiltration, a key component of this neuroimmune surveillance, into the axotomized facial motor nucleus and analyzed the changes in proinflammatory cytokines and the blood-brain barrier. Peripheral nerve transection led to a rapid influx of CD3-, CD11a (alphaL, LFA1alpha)- and CD44-immunoreactive T-cells into the axotomized mouse facial motor nucleus, with a first, low-level plateau 2-4 d after injury, and a second, much stronger increase at 14 d. These T-cells frequently formed aggregates and exhibited typical cleaved lymphocyte nuclei at the EM level. Immunohistochemical colocalization with thrombospondin (TSP), a marker for phagocytotic microglia, revealed aggregation of the T-cells around microglia removing neuronal debris. The massive influx of lymphocytes at day 14 was also accompanied by the synthesis of mRNA encoding IL1beta, TNFalpha, and IFN-gamma. There was no infiltration by the neutrophil granulocytes, and the intravenous injection of horseradish peroxidase also showed an intact blood-brain barrier. However, mice with severe combined immunodeficiency (SCID), which lack differentiated T- and B-cells, still exhibited infiltration with CD11a-positive cells. These CD11a-positive cells also aggregated around phagocytotic microglial nodules. In summary, there is a site-selective infiltration of activated T-cells into the mouse CNS during the retrograde reaction to axotomy. The striking aggregation of these lymphocytes around neuronal debris and phagocytotic microglia suggests an important role for the immune surveillance during neuronal cell death in the injured nervous system.

Inhibiting cell proliferation during formation of the glial scar: effects on axon regeneration in the CNS

“…Expression of TSP was up-regulated after the lesion: this protein is thought to be produced by reactive microglia and macrophages (Chamak et al, 1995;Möller et al, 1996;Raivich et al, 1998). Levels of expression were similar in all treatment groups, suggesting that the protein is expressed by non-dividing cells at the lesion site.…”

Role of microglia in CNS inflammation

“…However, at least in some model systems, T cell infiltration appears to be species specific. So in a facial nerve injury model, peripheral axotomy results in T cell infiltration into the facial nucleus of the mouse but not the rat (whose neurobiology seems closer to humans) [32]. Some authors even believe that specific T-cell subsets influence PD progression [29].…”

Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

“…While an aberrant immune process through the activation of pathogenic T cells may lead to an autoimmune neurodegenerative disease, boosting natural protective autoimmunity through regulatory T cells has been suggested as a neuroprotective strategy (Schwartz, 2003a;Schwartz, 2003b). Immune system function in glaucoma patients may partly be associated with immune surveillance (Raivich et al, 1998), which allows early contact of the immune system with the injury site for the removal of stressed or damaged cells and cellular debris. However, although T cell-mediated immune responses may initially be beneficial to limit neurodegeneration, a failure to properly control aberrant, stress-induced immune response likely converts the protective immunity into an autoimmune neurodegenerative process.…”