Since the dawn of modern immunology, immune responses within thecentral nervous system (CNS) have puzzled immunologists.
On onehand, the immune-privileged status of the CNS has been known for along time; along with the eye, the gonads, and the placenta, the CNSis among the few organs that accept grafted foreign cells morereadily than the rest of the body.1 On the other hand,the CNS has been known to be particularly susceptible to autoimmunedisease. The information neededto promote resolution of this question pertains to the rules thatgovern the entry of lymphocytes into CNS tissue. The detection ofthe TK-tsA transgene by in situ hybridization facilitatedreliable discrimination of the injected T cells from those of thehost. These cells were found predominantly in themesenchymal compartment near blood vessels and the meninges. Theautoreactive T cells that encountered their antigen in the CNSstayed. The injection ofpreactivated CNS antigen-reactive cells results in massive cellularinfiltration of the CNS, a reaction that peaked around day 6 in thecase of the MBP-
specific cells used by Bauer et al (Bauer et al, Table3). Although the specificity of the T cells that initiate thisinfiltration is highly defined in this experimental setup, thenature of the T cells that constitute the infiltrate had been amatter of controversy before these experiments. The study of T cellsthat infiltrate the target organ is among the most promisingapproaches to identifying T cells that mediate these diseases. Alternatively,the infiltrating cells might have originated in the host and beenrecruited to the inflamed site, in which case recruitment might berandom or might primarily involve CNS antigen-specific cells. They showed thatin the early stage (day 4) of EAE caused by TK-tsA-transgenic,MBP-specific cells, up to 50% of the T cells in the CNS aretransgene-positive and that their frequency drops to approximately25% at the peak of the disease on day 6 (Bauer et al, Table 3). Theremaining 50% to 70% of the T cells in the infiltrate were clearlyidentified as host-derived. Because the CNS antigen-specific T cellsinduced EAE they must have recognized autoantigen in the CNS andmust have secreted cytokines there. In light of all thesefindings, the immune privilege of the CNS could be defined asfollows. In this way the immune surveillance and protection of theCNS is warranted yet chronic inflammatory reactions that could causepermanent damage to the CNS are prevented. There is a further striking and novel observation reported in thepaper by Bauer et al, namely that apoptosis of T cells in the CNS isconfined to the neuroectodermal
parenchyma and is not seen in theconnective tissue compartment of this organ, the perivascular spaceand the meninges. For example, whereas the majority of theautoreactive T cells die in the neuroectodermal parenchyma, whichleads to recovery from the initial EAE attack, the autoreactive Tcells in the perivascular compartment might become stimulated toengage in clonal expansion by the endogenous antigen, giving rise toa new generation of effector cells. As in the primary episode of thedisease, the cells that enter the neuroectodermal parenchyma willdie and the second episode of EAE will also become self-limiting. Inthis manner relapses and remissions of the disease could be causedby the fluctuation of new waves of T cell responses generated in theCNS mesenchyma followed by their decimation in the parenchyma. However,the apoptosis pathway might be the more common one.