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Identification of T Cell Ligands in a Library of Peptides Covalently Attached to HLA-DR4

Eric Boen^*, Angie R. Crownover^*, Mary McIlhaney^*, Alan J. Korman^1,* and Jerry Bill^2,

^* Nexstar Pharmaceuticals, Boulder, CO 80301; and Division of Allergy and Clinical Immunology, University of Colorado Health Sciences Center, Denver, CO 80262

While T cells have been clearly implicated in a number of disease processes including autoimmunity, graft rejection, and atypical immune responses, the precise Ags recognized by the pathogenic T cells have often been difficult to identify. This has particularly been true for MHC class II-restricted CD4⁺ T cells. Although such cells can be demonstrated to have undergone clonal expansion at sites of pathology, they are frequently difficult to establish as stable T cell clones. Furthermore, in general, larger peptides in higher concentrations are required to stimulate CD4⁺ T cells than CD8⁺ T cells, which makes some of the techniques developed to identify CD8⁺ T cell Ags impractical. To circumvent some of these problems, we developed a model system consisting of two parts. The first part involves the construction of an indicator T cell hybridoma expressing a chimeric TCR comprised of murine constant regions and human variable regions specific for influenza hemagglutinin 307–319 presented by DR4. The second part consists of a library of fibroblasts each expressing multiple peptides as amino terminal covalent extensions of the ß-chain of HLA-DR4 (DRA1*0101, DRB1*0401). Using this model system, we screened 100,000 peptides and identified three novel peptides stimulatory for the HA1.7 TCR. While there is some convergence at residues known to be important for T cell recognition, all three peptides differ markedly from each other and bear little resemblance to wild-type hemagglutinin 307–319.

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