title: Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells.
abstract: Thymocyte development is a tightly controlled multi-step process involving selective elimination of self-reactive and non-functional T cells by apoptosis. This developmental process depends on signaling by Notch, IL-7 and active glucose metabolism. In this study, we explored the requirement of glucose for thymocyte survival and found that in addition to metabolic regulation, glucose leads to the expression of anti-apoptotic genes. Under hyperglycemic conditions, both mouse and human thymocytes demonstrate enhanced survival. We show that glucose-induced anti-apoptotic genes are dependent on NF-κB p65 because high glucose is unable to attenuate normal ongoing apoptosis of thymocytes isolated from p65 knockout mice. Furthermore, we demonstrate that in vivo hyperglycemia decreases apoptosis of thymocytes allowing for survival of potentially self-reactive thymocytes. These results imply that hyperglycemic conditions could contribute to the development of autoimmunity through dysregulated thymic selection.
authors.affiliation: Division of Biology, California Institute of Technology, 1200 California Boulevard, Pasadena, CA 91125, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ramakrishnan
authors.forename: D A
authors.initials: DA
authors.lastname: Kahn
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D002470:Cell Survival; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013961:Thyroid Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020569:Proto-Oncogene Proteins c-rel; D047888:Receptors, Tumor Necrosis Factor, Type I; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D005947:Glucose