J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/05/1651/10 $2.00
Volume 185, Number 9, May 5, 1997 1651-1660

Identification of High Potency Microbial and Self Ligands for a Human Autoreactive Class II-restricted T Cell Clone

By Bernhard Hemmer,^* Burkhard T. Fleckenstein,^§ Marco Vergelli,^* Günther Jung, Henry McFarland,^* Roland Martin,^* and Karl-Heinz Wiesmüller^§

From the ^* Neuroimmunology Branch, National Institue of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1400;  Institut für Organische Chemie, Universität Tübingen, 72076 Tübingen, Germany; ^§ Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen, 72762 Reutlingen, Germany; and  Department of Neurology, Tübingen University Medical School, 72076 Tübingen, Germany

CD4⁺ class II-restricted T cells specific for self antigens are thought to be involved in the pathogenesis of most human autoimmune diseases and molecular mimicry between foreign and self ligands has been implicated as a possible mechanism for their activation. In this report we introduce combinatorial peptide libraries as a powerful tool to identify cross-reactive ligands for these T cells. The antigen recognition of a CD4⁺ T cell clone (TCC) specific for myelin basic protein peptide (MBP) (86-96) was dissected by the response to a set of 220 11-mer peptide sublibraries. Based on the results obtained with the libraries for each position of the antigen, artificial peptides were found that induced proliferative responses at much lower concentrations than MBP(86-96). In addition stimulatory ligands derived from protein sequences of self and microbial proteins were identified, some of them even more potent agonists than MBP(86-96). These results indicate that: (a) for at least some autoreactive CD4⁺ T cells antigen recognition is highly degenerate; (b) the autoantigen used to establish the TCC represents only a suboptimal ligand for the TCC; (c) a completely random and unbiased approach such as combinatorial peptide libraries can decrypt the spectrum of stimulatory ligands for a T cell receptor (TCR).

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