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1.
J Immunol ; 166(2): 908-17, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11145667

ABSTRACT

Nonobese diabetic (NOD) mice spontaneously develop insulitis and destruction of pancreatic islet beta cells similar to type 1 diabetes mellitis in humans. Insulitis also occurs in the BDC2.5 TCR transgenic line of NOD mice that express the rearranged TCR alpha- and beta-chain genes of a diabetogenic NOD CD4 T cell clone. When activated with syngeneic islet cells in culture, BDC2.5 T cells adoptively transfer disease to NOD recipients, but the identity of the islet cell Ag responsible for pathogenicity is not known. To characterize the autoantigen(s) involved, BDC2.5 T cells were used to screen a combinatorial peptide library arranged in a positional scanning format. We identified more than 100 decapeptides that stimulate these T cells at nanomolar concentrations; they are then capable of transferring disease to NOD-scid mice. Surprisingly, some of the peptides include sequences similar (8 of 10 residues) to those found within the 528-539 fragment of glutamic acid decarboxylase 65. Although this 12-mer glutamic acid decarboxylase 65 fragment is only slightly stimulatory for BDC2.5 T cells (EC(50) > 100 microM), a larger 16-mer fragment, 526-541, shows activity in the low micromolar range (EC(50) = 2.3 microM). Finally, T cells from prediabetic NOD mice respond spontaneously to these peptide analogs in culture; this finding validates them as being related to a critical autoantigen involved in the etiology of spontaneous diabetes and indicates that their further characterization is important for a better understanding of underlying disease mechanisms.


Subject(s)
Diabetes Mellitus, Type 1/enzymology , Diabetes Mellitus, Type 1/immunology , Glutamate Decarboxylase/immunology , Histocompatibility Antigens Class II/immunology , Isoenzymes/immunology , Lymphocyte Activation/immunology , Peptide Fragments/immunology , T-Lymphocytes/enzymology , T-Lymphocytes/immunology , Adoptive Transfer , Amino Acid Sequence , Animals , Cells, Cultured , Diabetes Mellitus, Type 1/etiology , Female , Glutamate Decarboxylase/isolation & purification , Glutamate Decarboxylase/metabolism , Isoenzymes/isolation & purification , Isoenzymes/metabolism , Ligands , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Molecular Sequence Data , Peptide Fragments/isolation & purification , Peptide Fragments/metabolism , Peptide Library , Prediabetic State/immunology , Sequence Homology, Amino Acid , T-Lymphocytes/transplantation
2.
J Immunol ; 163(12): 6424-34, 1999 Dec 15.
Article in English | MEDLINE | ID: mdl-10586032

ABSTRACT

Recent studies have demonstrated the utility of synthetic combinatorial libraries for the rapid identification of peptide ligands that stimulate clonotypic populations of T cells. Here we screen a decapeptide combinatorial library arranged in a positional scanning format with two different clonotypic populations of CD4+ T cells to identify peptide epitopes that stimulate proliferative responses by these T cells in vitro. An extensive collection of mimic peptide sequences was synthesized and used to explore the fine specificity of TCR/peptide/MHC interactions. We also demonstrate that many of these deduced ligands are not only effective immunogens in vivo, but are capable of inducing T cell responses to the original native ligands used to generate the clones. These results have significant implications for considerations of T cell specificity and the design of peptide vaccines for infectious disease and cancer using clinically relevant T cell clones of unknown specificity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Lymphocyte Activation , Peptide Library , Peptides/immunology , Amino Acid Sequence , Animals , CD4-Positive T-Lymphocytes/metabolism , Clone Cells , Columbidae , Cytochrome c Group/immunology , Cytochrome c Group/metabolism , Epitopes, T-Lymphocyte/metabolism , Female , Humans , Ligands , Mice , Mice, Inbred C57BL , Molecular Mimicry/immunology , Molecular Sequence Data , Myelin Basic Protein/immunology , Peptides/metabolism , Rats , Rats, Inbred Lew
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