Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes.
Type 1 diabetes, insulin-dependent diabetes mellitus (IDDM) results from autoimmune T cell-dependent destruction of insulin producing beta-cells in the pancreatic islets of Langerhans. T cells from recent-onset IDDM patients specifically proliferate to beta cell membrane Ag enriched fractions, containing the mitochondrial 38 kD islet antigen (Imogen). Recently, we identified a peptide epitope (Imogen p55-70) that is recognized by a 38 kD-specific, Th1 clone from an IDDM patient. In animal models of autoimmune diseases, altered self peptide ligands (APL) have been used effectively in peptide-based immune prevention or therapy. No such APL, however, have been reported so far that can modulate autoreactive T-cell responses in IDDM. Here, we have designed APL of p55-70. These APL efficiently downregulate in vitro activation of the 38 kD-specific Th1 clone induced by either p55-70 or by native beta cell autoantigens. Self peptide reactive T-cell proliferation could be inhibited only when APL and the self peptide were present on the same APC. Unrelated peptides with equal HLA-DR binding affinity were not effective, excluding simple MHC competition as the mechanism for T-cell modulation. APL triggered upregulation of CD69 and CD25 expression, but not T-cell proliferation, TCR down-modulation or T-cell anergy. Thus, the p55-70 APL inhibit beta cell autoantigen-induced activation of an Imogen-reactive T-cell clone derived from an IDDM patient, by acting as partial TCR agonists that inhibit TCR down-modulation.
Geluk
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Department of Immunohematology and Blood Bank, Leiden University Medical Center, The Netherlands. Geluk@rullf2.Medfac.Leidenuniv.nl
van Meijgaarden
K E
KE
Roep
B O
BO
Ottenhoff
T H
TH
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D015536:Down-Regulation; D018984:Epitopes, T-Lymphocyte / Q000187:drug effects* / Q000276:immunology*; D015798:HLA-DR1 Antigen / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D037181:Lectins, C-Type; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012269:Ribosomal Proteins; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D037181:Lectins, C-Type; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D012269:Ribosomal Proteins; D000099192:CD69 Antigens; C097896:MRPS31 protein, human