Because Notch often acts in concert with other signaling pathways, it is able to regulate a diverse set of biological processes in a cell-context dependent manner. In lymphocytes, Notch is essential for specifying the T cell fate and for promoting early stages of T cell differentiation. At later stages of development, Notch signaling is proposed to direct CD4 versus CD8 T lineage commitment. This hypothesis has been challenged by recent studies of conditional Presenilin-deficient mice showing that Notch promotes the selection and maturation of CD4 and CD8 T cells by potentiating TCR signal transduction in immature thymocytes. While similar conclusions have not been reported with conditional mutation of other downstream mediators of Notch activation, it appears that functional inhibition may not have been achieved at a comparable stage of development and/or analogous issues have not been addressed. The differences also question whether in thymocytes Notch signals only through the canonical pathway. Further study of conditional mutants, signaling intermediates, and transcriptional regulators are needed to elucidate how Notch facilitates TCR signaling in generating mature T cells.

• Z01 AI000486/ImNIH/Intramural NIH HHS/United States