Progression of intracranial glioma disrupts thymic homeostasis and induces T-cell apoptosis in vivo.
The thymus is the site where all T-cell precursors develop, mature, and subsequently leave as mature T-cells. Since the mechanisms that mediate and regulate thymic apoptosis are not fully understood, we utilized a syngenic GL261 murine glioma model to further elucidate the fate of T-cells in tumor bearing C57BL/6 mice. First, we found a dramatic reduction in the size of the thymus accompanied by a decrease in thymic cellularity in response to glioma growth in the brains of affected mice. There was a marked reduction of double positive subset and an increase in the frequency of CD4(+) and CD8(+) single positive T-cell subsets. Analysis of double negative thymocytes showed an increase in the accumulation of CD44(+) cells. In contrast, there was a marked loss of CD44 and CD122 expression in CD4(+) and CD8(+) subsets. The growth of intracranial tumors was also associated with decreased levels of HO-1, a mediator of anti-apoptotic function, and increased levels of Notch-1 and its ligand, Jagged-1. To determine whether thymic atrophy could be due to the effect of Notch and its ligand expression by glioma in vivo, we performed a bone marrow transplant experiment. Our results suggest that Notch-1 and its ligand Jagged-1 can induce apoptosis of thymocytes, thereby influencing thymic development, immune system homeostasis, and function of the immune cells in a model of experimental glioma.
Andaloussi
Abdeljabar El
AE
The Brain Tumor Center, The University of Chicago, 5841 S. Maryland Ave MC 3026, Chicago, IL, 60637, USA.
Han
Yu
Y
Lesniak
Maciej S
MS
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D018450:Disease Progression; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006706:Homeostasis; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D051547:Heme Oxygenase-1