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 (αL, LFA1α)- 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 IL1β, TNFα, and IFN-γ. 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.