Tolerating the Nervous System: A Delicate Balance

Experimental allergic encephalomyelitis (EAE) is an animal model of multiple sclerosis that is induced by immunization with myelin antigens (1). The ability to generate EAE by activating myelin-specific T cells in the periphery of healthy animals demonstrates that central and peripheral mechanisms of tolerance are incomplete for these self-anti-gens. This lack of T cell tolerance toward myelin proteins was initially thought to be due to restricted expression of these antigens behind the blood–brain barrier. Recent data demonstrate that T cell epitopes from the two most abundant proteins in myelin, proteolipid protein (PLP) and my-elin basic protein (MBP), are expressed not only within the central nervous system (CNS) and peripheral nervous system but within the thymus, spleen, and lymph nodes as well (2–6). In this issue of The Journal of Experimental Medicine (7), as well as in a related paper in Nature Medicine (8), the question of whether PLP expression in the thymus shapes the PLP-specific TCR repertoire is explored. PLP exists in two isoforms: PLP is the full-length form, and DM20 is a shorter form generated by alternative splicing that lacks 35 amino acids (9). Although transcripts corresponding to both isoforms are detected in the thymus, Anderson et al. (7) and Klein et al. (8) report that the DM20 transcript is expressed intrathymically at much higher levels than the full-length PLP transcript. These findings suggest that determinants within DM20 may be much more effective at inducing central tolerance than determinants found only in the larger form of PLP. Klein et al. demonstrate that T cells specific for several determinants that are shared between PLP and the DM20 do indeed undergo tolerance in wild-type mice. Using thy-mic grafts and bone marrow chimeras, they show that both thymic epithelial cells and bone marrow–derived cells mediate tolerance induction in PLP-specific T cells. Anderson et al. make the striking observation that T cells specific for a determinant that is unique to the larger form of PLP and missing from DM20 (PLP 139–151) are not tolerized in SJL mice. Both groups conclude that the level of thymic expression of DM20 is sufficient to mediate tolerance to epitopes in this isoform but that thymic expression of PLP is not sufficient to induce tolerance to the unique sequences in the PLP isoform. The ability to detect responses to PLP 139–151 in lymph node cells from SJL mice indicates that these T cells not only escape central tolerance …