Journal
JOURNAL OF IMMUNOLOGY
Volume 187, Issue 11, Pages 5921-5930Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100746
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Funding
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK055969]
- National Institutes of Health, Diabetes and Endocrinology Research Core [P30 DK057516]
- National Institute of Allergy and Infectious Diseases [U519 A1050864-08]
- Juvenile Diabetes Foundation [4-2007-1056, 17-2010-744]
- Brehm Coalition
- Children's Diabetes Foundation
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Class II major histocompatibility molecules are the primary susceptibility locus for many autoimmune disorders, including type 1 diabetes. Human DQ8 and I-A(g7), in the NOD mouse model of spontaneous autoimmune diabetes, confers diabetes risk by modulating presentation of specific islet peptides in the thymus and periphery. We used an in silico molecular docking program to screen a large druglike chemical library to define small molecules capable of occupying specific structural pockets along the I-A(g7) binding groove, with the objective of influencing presentation to T cells of the autoantigen insulin B chain peptide consisting of amino acids 9-23. In this study we show, using both murine and human cells, that small molecules can enhance or inhibit specific TCR signaling in the presence of cognate target peptides, based upon the structural pocket targeted. The influence of compounds on the TCR response was pock et dependent, with pocket 1 and 6 compounds inhibiting responses and molecules directed at pocket 9 enhancing responses to peptide. At nanomolar concentrations, the inhibitory molecules block the insulin B chain peptide consisting of amino acids 9-23, endogenous insulin, and islet-stimulated T cell responses. Glyphosine, a pocket 9 compound, enhances insulin peptide presentation to T cells at concentrations as low as 10 nM, upregulates IL-10 secretion, and prevents diabetes in NOD mice. These studies present a novel method for identifying small molecules capable of both stimulating and inhibiting T cell responses, with potentially therapeutic applications. The Journal of Immunology, 2011,187: 5921-5930.
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