Dataset Information

Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2K(d) that stimulates CD8 T cells in insulin-dependent diabetes mellitus.

ABSTRACT: The recognition of MHC-peptide complexes by T cells is governed by structural considerations that are determined by the sequences of the individual components and their interaction with each other. We have studied the function of a highly diabetogenic CD8 T cell clone that is specific for insulin B15-23:H-2K(d). We have then related this to modeled MHC-peptide structures. The native peptide binds poorly to H-2K(d), because of the small glycine residue at peptide position p9 that is incapable of productive interactions with the hydrophobic residues of pocket F. In addition, electrostatic repulsions between the peptide glutamate residue at position 7 and 152D of the MHC molecule heavy chain contribute to the poor binding. However, B chain peptide 15-23 bound to K(d) shows excellent T cell stimulation and the induction of CD8 cytotoxic T cells. Peptide substitution has also shown that p6G is likely to be a T cell antigen receptor interaction site. Our studies have shown that the predictions seen in the models correlate closely with the observed effects in functional assays and provide insight into how this peptide, which would not be predicted to stimulate these cells on H-2K(d) binding studies alone, could activate such highly pathogenic T cells.

SUBMITTER: Wong FS

PROVIDER: S-EPMC122807 | biostudies-literature | 2002 Apr

REPOSITORIES: biostudies-literature

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Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2K(d) that stimulates CD8 T cells in insulin-dependent diabetes mellitus.

Wong F Susan FS Moustakas Antonis K AK Wen Li L Papadopoulos George K GK Janeway Charles A CA

Proceedings of the National Academy of Sciences of the United States of America 20020409 8

The recognition of MHC-peptide complexes by T cells is governed by structural considerations that are determined by the sequences of the individual components and their interaction with each other. We have studied the function of a highly diabetogenic CD8 T cell clone that is specific for insulin B15-23:H-2K(d). We have then related this to modeled MHC-peptide structures. The native peptide binds poorly to H-2K(d), because of the small glycine residue at peptide position p9 that is incapable of ...[more]

PMID: 11943852

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Project description:Background: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.3±5.8 years, BMI 29.8±3.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 °C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.40±0.29 to 0.63±0.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.9±4.1 to 20.5±6.9 μmol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes. Microarray analysis was performed on abdominal subcutaneous white adipose tissue samples from human type 2 diabetic patients before, and after 10 days of cold acclimation. A total of 14 samples, from 7 subjects, were used for the microarray analysis.

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Dataset Information

Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2K(d) that stimulates CD8 T cells in insulin-dependent diabetes mellitus.

Publications

Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2K(d) that stimulates CD8 T cells in insulin-dependent diabetes mellitus.

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