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

Eli Sercarz, Emanual Michael Maverakis, Peter Van Den Elzen, Loui Madakamutil, Vipin Kumar, Powrie, Bach, Miller

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Abstract

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 Vβ8.2, Jβ2.7 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 Vβ 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 Vβ8.2 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.

Original languageEnglish (US)
Pages (from-to)165-176
Number of pages12
JournalNovartis Foundation Symposium
Volume252
StatePublished - 2003

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sercarz, E., Maverakis, E. M., Van Den Elzen, P., Madakamutil, L., Kumar, V., Powrie, Bach, & Miller (2003). Seven surprises in the TCR-centred regulation of immune responsiveness in an autoimmune system. Novartis Foundation Symposium, 252, 165-176.