Loss of Canonical Notch Signaling Affects Multiple Steps in NK Cell Development in Mice

Abstract

Within the hematopoietic system, the Notch pathway is critical for promoting thymic T cell development and suppressing the B and myeloid lineage fates; however, its impact on NK lymphopoiesis is less understood. To study the role of Notch during NK cell development in vivo, we investigated different NK cell compartments and function in Rbp-Jk fl/fl Vav-Cre tg/+ mice, in which Rbp-Jk, the major transcriptional effector of canonical Notch signaling, was specifically deleted in all hematopoietic cells. Peripheral conventional cytotoxic NK cells in Rbp-Jk-deleted mice were significantly reduced and had an activated phenotype. Furthermore, the pool of early NK cell progenitors in the bone marrow was decreased, whereas immature NK cells were increased, leading to a block in NK cell maturation. These changes were cell intrinsic as the hematopoietic chimeras generated after transplantation of Rbp-Jk-deficient bone marrow cells had the same NK cell phenotype as the Rbp-Jk-deleted donor mice, whereas the wild-type competitors did not. The expression of several crucial NK cell regulatory pathways was significantly altered after Rbp-Jk deletion. Together, these results demonstrate the involvement of canonical Notch signaling in regulation of multiple stages of NK cell development.

Transcriptional Regulation of Natural Killer Cell Development and Functions

“…After prenatal hematopoiesis occurs in the fetal liver, the Notch signaling pathway is essential to promote T cell commitment in the thymus and suppress alternative lineage fate potentials, including B cells, DCs, and myeloid cells [126][127][128]. However, some studies suggest that Notch signaling does not restrict NK cell lineage specification [129][130][131]. In the absence of lineage specifying factors, such as Pax5 in B cells or Bcl11 in T cells, pro-B cells or thymocytes can be reprogrammed into NK cells when cultured with Notch ligands (Bcl11 is a target of Notch1 signaling) [132,133].…”

“…In the absence of lineage specifying factors, such as Pax5 in B cells or Bcl11 in T cells, pro-B cells or thymocytes can be reprogrammed into NK cells when cultured with Notch ligands (Bcl11 is a target of Notch1 signaling) [132,133]. Further studies in Vav1-Cre-Rbp-JK fl/fl mice showed that not only is the number of early BM NKPs reduced, but the maturation of splenic NK cells is also blocked [129][130][131]. Rbp-JK is an essential transcriptional effector in the Notch signaling pathway [113].…”

“…Rbp-JK is an essential transcriptional effector in the Notch signaling pathway [113]. The perturbed NK cell development may result from the significantly reduced expression of Ets-1 and Ikaros in NKPs of Rbp-JK-deficient mice [129][130][131]. In addition, activated Notch signaling can increase the cytotoxic effect of NK cells by directly enhancing KIR expression [134].…”

“…Cancers 2020, 12, x 7 of 33 suggest that Notch signaling does not restrict NK cell lineage specification [129][130][131]. In the absence of lineage specifying factors, such as Pax5 in B cells or Bcl11 in T cells, pro-B cells or thymocytes can be reprogrammed into NK cells when cultured with Notch ligands (Bcl11 is a target of Notch1 signaling) [132,133].…”

Dazed and Confused: NK Cells

“…Collective reports have demonstrated that iNK cells in mouse bone marrow and periphery can express Ly49 receptors, CD49a, CD90, TRAIL, CD69, and Eomes, and lack CD49b expression (3, 21, 29–31). Upon adoptive transfer into lymphopenic mice, iNK cells can induce CD49b expression and retain Eomes expression (3).…”