Specifically, it was found that addition of RA during Flt3L-driven DC development skewed the culture drastically toward the SIRPαhi CD11bhi DC subtype, although it was not examined whether ESAM was also expressed under these conditions. Whether the concomitant reduction in the culture equivalents of the CD8hi/XCR1hi lineage (SIRPαlo CD11blo), and the reduced proportion of CD8+ DCs in mice kept on a vitamin A-rich diet indicates that RA also actively represses the development of CD8hi/XCR1hi DCs is an exciting possibility that remains to be tested. Taken together Beijer et
al. [13] demonstrate that RA signaling is necessary for the development of the ESAMhi CD11bhi DC subset within Ceritinib cost the spleen. These insights bring into focus a number of questions. For example, at what developmental stage are DCs subjected to RA conditioning? In this regard, it is interesting to note that hematopoietic stem cells in the bone marrow are among the few leukocytes that produce RA [19]. Analogous to the exposure of CD103+ DCs to RA in the intestine rather than in lymphoid organs [15], it is possible that pre-DCs would be exposed to RA in the bone marrow
prior to their migration Sunitinib in vivo toward the spleen (Fig. 1A). Given that the proportion of circulating pre-DCs was unaffected in the absence of vitamin A, such a conditioning effect of RA would have to be regulated at a qualitative level rather than simply by altering the precursor product relationship numerically. Nevertheless, whether these events take place at the pre-DC level in the bone marrow or occur in the spleen requires further investigation. Another consideration arising from these findings relates to the potential mechanism by which RA signaling promotes the development of ESAMhi CD11bhi DCs. Given that ESAMhi CD11bhi DC differentiation is dependent upon Notch 2 receptor signaling, an interesting explanation maybe linked to RA
regulating the expression of Notch 2 receptor and/or its ligands (Fig. 1B). below Indeed, it has recently been demonstrated that Raldh2-deficient mice, which are unable to convert vitamin A to RA, have diminished Notch signaling in developing neural tissues [20]. Thus, it is possible that RA signaling directly drives the expression of Notch 2 receptor and/or the ligands, and in this fashion, is necessary for the development of ESAMhi CD11bhi DCs. It will be interesting to examine whether the RA-dependent DC subsets express differential levels of Notch 2 receptor relative to other DC subsets. Similarly, future studies should investigate whether the Notch 2 receptor and/or its ligands contain RA-responsive elements within their promoter regions and are thereby directly regulated by RA. An alternative, although not mutually exclusive, mechanistic explanation may be that RA conditions pre-DCs to localize to distinct areas within the spleen that favor the differentiation of ESAMhi CD11bhi DCs (Fig. 1B).