Notch2 Receptor Signaling Controls Functional Differentiation of Dendritic Cells in the Spleen and Intestine

Abstract

Summary Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b+ DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esamhi DC subset required lymphotoxin beta receptor signaling, proliferated in situ and facilitated CD4+ T cell priming. The Notch-independent Esamlo DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b+ CD103+ DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4+ T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b+ DC subsets in the spleen and intestine.

Differentiation of CD11c + CX 3 CR1 + cells in the small intestine requires Notch signaling

“…Accumulating evidence indicates that Notch signaling is crucial for the development of immune cells and for the functional differentiation of T cells (12)(13)(14)(15)(16)(17)(18)(19). Recent studies have revealed that Notch signaling also regulates the development of DCs in the spleen and intestine (20) (21,22). These data indicate that Rbpj regulates the survival of CD8 − DCs in the spleen and that Notch2 signaling controls CD11b + CD103 + DCs in the intestinal LP.…”

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…Gut and gut-associated lymphoid tissues also contain CD11b + CD103 + cells (Bogunovic et al, 2009;Varol et al, 2009). These migratory DC subsets also have quite unique functions (Kaplan et al, 2005;Bedoui et al, 2009;King et al, 2010;Lewis et al, 2011;Shklovskaya et al, 2011). DCs represent a rare type of leukocyte in lymphoid tissues.…”

CD11b+DCs rediscovered: implications for vaccination

“…The latter hypothesis is supported by the fact that CD11b + DCs show tissuedependent TF requirements, which may reflect a certain degree of genetic imprinting on DC precursors by the host tissue. In fact, splenic CD11b + ESAM + DCs are dependent on NOTCH2 and RELB, but not on IRF4, while the CD11b + CD103 + DCs in the gut lamina propria are dependent on NOTCH2, RELB and IRF4 [6,8,10]. In contrast, lung CD11b + DCs differentiate independently of NOTCH2 and RELB but do require IRF4 [8].…”

“…CD8a + /CD103 + DCs are required to efficiently cross-present antigen and stimulate CD8 + T cell immunity through secretion of IL-12, thereby also promoting Th1 differentiation and underlining their crucial role in the defense against intracellular pathogens [1]. In contrast, dissecting the relationship between NLT and LT CD11b + DC populations has proven difficult: phenotypically, while spleen CD11b + DCs express CD4 and endothelial cellselective adhesion molecule (ESAM) [6], NLT CD11b + DCs do not. Ontogenetically, NLT CD11b + DCs (expressing MHC-II, CD11c and CD11b) were thought to arise from both bone marrow (BM) DC-specific progenitors and monocytes, with partial dependence on both FLT3 and the macrophage/monocyte lineage growth factor receptor, CSF-1R, for their differentiation [7].…”

“…However, reanalysis of the CD11b + DC compartment using CD24 (DC marker) and CD64/MerTK (macrophage markers) improved discrimination of DCs and macrophages, revealing the true bona fide DC nature of the CD24 + CD11b + population, which is purely dependent on FLT3 for its differentiation [8,9]. CD11b + DCs were also found to depend on various other transcription factors (TFs) such as NOTCH2, RELB and IRF4 [6,[8][9][10]. These recent developments illustrate the importance of analyses of growth factor and TF requirements of DC subsets in advancing our understanding of their inter-relationships.…”