The Fate of T Cells in the Brain: Veni, Vidi, Vici and Veni, Mori

Abstract

Since the dawn of modern immunology, immune responses within the central nervous system (CNS) have puzzled immunologists. On one hand, the immune-privileged status of the CNS has been known for a long time; along with the eye, the gonads, and the placenta, the CNS is among the few organs that accept grafted foreign cells more readily than the rest of the body. 1 On the other hand, the CNS has been known to be particularly susceptible to autoimmune disease. The first and best characterized autoimmune model, experimental allergic encephalomyelitis (EAE), which resembles multiple sclerosis (MS), is the result of an autoimmune attack by T lymphocytes on the CNS. 2 A report on EAE in this issue 3 by Bauer et al provides data of exceptional clarity that should help in understanding this apparent contradiction. Neuroantigen-specific T cells, which can mount an autoimmune attack against the CNS, are detectable in healthy individuals. This is particularly well established for T cells that are specific for myelin basic protein (MBP), the best-characterized target antigen in the CNS. Studies using MBP-specific T cell receptor-transgenic mice suggested that these T cells normally ignore the autoantigen. 4-6 Like lymphocytes that have not encountered their antigen before, they retain a naive/resting phenotype. Such T cells dramatically change their behavior as soon as they become activated in the course of an immune response; they start to infiltrate the CNS and cause inflammatory damage there. In experimental models EAE is initiated either by immunization with a CNS antigen (for active EAE) or by in vitro injection of activated CNS antigen-specific T cells (for passive EAE, the model used by Bauer et al). In MS, infections with crossreactive microorganisms are thought to initiate the autoimmune attack. It remains unclear why activated myelin-reactive T cells “see” and attack the autoantigen that resting T cells with the same specificity had ignored. The information needed to promote resolution of this question pertains to the rules that govern the entry of lymphocytes into CNS tissue. This issue was addressed by Bauer et al. They injected into rats congenic T cells specific for either various CNS “self” antigens (Bauer et al, Table 1) or for the irrelevant “foreign” antigen ovalbumin (OVA). To distinguish clearly between injected T cells with a defined specificity and activation state and recruited host-derived T cells of unknown specificity and activation state, the authors took advantage of a TK-tsa-transgenic model. The detection of the TK-tsA transgene by in situ hybridization facilitated reliable discrimination of the injected T cells from those of the host.