AUTHOR=Dongre Anushka , Surampudi Lalitha , Lawlor Rebecca G., Fauq Abdul H., Miele Lucio , Golde Todd E., Minter Lisa M., Osborne Barbara A. TITLE=Non-Canonical Notch Signaling Drives Activation and Differentiation of Peripheral CD4+ T Cells JOURNAL=Frontiers in Immunology VOLUME=5 YEAR=2014 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00054 DOI=10.3389/fimmu.2014.00054 ISSN=1664-3224 ABSTRACT=

Cleavage of the Notch receptor via a γ-secretase, results in the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-Jκ, resulting in the activation of downstream target genes. This canonical Notch signaling pathway has been documented to influence T cell development and function. However, the mechanistic details underlying this process remain obscure. In addition to RBP-Jκ, the intra-cellular domain of Notch also interacts with other proteins in the cytoplasm and nucleus, giving rise to the possibility of an alternate, RBP-Jκ independent Notch pathway. However, the contribution of such RBP-Jκ independent, “non-canonical” Notch signaling in regulating peripheral T cell responses is unknown. In this report, we specifically demonstrate the requirement of Notch1 for regulating signal strength and signaling events distal to the T cell receptor in peripheral CD4+ T cells. By using mice with a conditional deletion in Notch1 or RBP-Jκ, we show that Notch1 regulates activation and proliferation of CD4+ T cells independently of RBP-Jκ. Furthermore, differentiation to TH1 and iTreg lineages although Notch dependent, is RBP-Jκ independent. Our striking observations demonstrate that many of the cell-intrinsic functions of Notch occur independently of RBP-Jκ. Such non-canonical regulation of these processes likely occurs through NF-κ B. This reveals a previously unknown, novel role of non-canonical Notch signaling in regulating peripheral T cell responses.