Notch regulates cytolytic effector function in CD8+ T cells.
The maturation of naive CD8(+) T cells into effector CTLs is a critical feature of a functional adaptive immune system. Development of CTLs depends, in part, upon the expression of the transcriptional regulator eomesodermin (EOMES), which is thought to regulate expression of two key effector molecules, perforin and granzyme B. Although EOMES is important for effector CTL development, the precise mechanisms regulating CD8(+) effector cell maturation remains poorly understood. In this study, we show that Notch1 regulates the expression of EOMES, perforin, and granzyme B through direct binding to the promoters of these crucial effector molecules. By abrogating Notch signaling, both biochemically as well as genetically, we conclude that Notch activity mediates CTL activity through direct regulation of EOMES, perforin, and granzyme B.
Cho
Ok Hyun
OH
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Shin
Hyun Mu
HM
Miele
Lucio
L
Golde
Todd E
TE
Fauq
Abdul
A
Minter
Lisa M
LM
Osborne
Barbara A
BA
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054353:Perforin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
C491198:Eomes protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D020825:T-Box Domain Proteins; D054353:Perforin; D053829:Amyloid Precursor Protein Secretases; D053804:Granzymes