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More MS news articles for November 2003

Seven surprises in the TCR-centred regulation of immune responsiveness in an autoimmune system

Novartis Found Symp. 2003;252:165-71; discussion 171-6, 203-10
Sercarz E, Maverakis E, van den Elzen P, Madakamutil L, Kumar V.
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.

Self-reactivity is potentially so devastating to the organism that a variety of regulatory devices have evolved to control it.

One broadly used strategy is that employing the processed T cell receptor (TCR) as a target for TCR-specific regulatory cells.

In several autoimmune models, feedback regulation employing both CD4+ and CD8+ T cells of TCR specificity can be shown to occur and to account for remission from the transient disease state, or for its prevention.

We will focus here on the experimental autoimmune encephalomyelitis (EAE) model in the B10.PL (H-2u) mouse.

In this model, the acetylated 1-9 N-terminal antigenic determinant from myelin basic protein (MBP) induces a transient paralytic disease owing to the activation of self-directed, high-affinity, CD4+ T cells.

Although the response is multiclonal, a particularly aggressive member of this repertoire, bearing a Vbeta8.2,Jbeta2.7 receptor, which we have termed a 'driver clone', appears to be largely responsible for the disease process.

A CD4+ T cell directed against a TCR determinant in the framework region of the Vbeta chain, and a CD8+ T cell directed against an upstream, distinct framework determinant, both of which are necessary for regulation, bring about a reversal of the disease process.

To accomplish this, there must be a Th1 milieu during the induction of regulation, which is provided in part by the CD4+ regulatory cells themselves.

To act as a target, the Vbeta8.2 MBP-reactive T cell must be activated, and the Th1 driver clone(s) is down-regulated via apoptotic killing, leaving a group of Th2, MBP-specific clones of weak affinity, which themselves may help in perpetuating long-term regulation.

Similar results are also found in the collagen arthritis and NOD diabetes models.