CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

Abstract

Classical CD16− vs intermediate/nonclassical CD16+ monocytes differ in their homing potential and biological functions, but whether they differentiate into dendritic cells (DCs) with distinct contributions to immunity against bacterial/viral pathogens remains poorly investigated. Here, we employed a systems biology approach to identify clinically relevant differences between CD16+ and CD16− monocyte-derived DCs (MDDCs). Although both CD16+ and CD16− MDDCs acquire classical immature/mature DC markers in vitro, genome-wide transcriptional profiling revealed unique molecular signatures for CD16+ MDDCs, including adhesion molecules (ITGAE/CD103), transcription factors (TCF7L2/TCF4), and enzymes (ALDH1A2/RALDH2), whereas CD16− MDDCs exhibit a CDH1/E-cadherin+ phenotype. Of note, lipopolysaccharides (LPS) upregulated distinct transcripts in CD16+ (eg, CCL8, SIGLEC1, MIR4439, SCIN, interleukin [IL]-7R, PLTP, tumor necrosis factor [TNF]) and CD16− MDDCs (eg, MMP10, MMP1, TGM2, IL-1A, TNFRSF11A, lysosomal-associated membrane protein 1, MMP8). Also, unique sets of HIV-modulated genes were identified in the 2 subsets. Further gene set enrichment analysis identified canonical pathways that pointed to “inflammation” as the major feature of CD16+ MDDCs at immature stage and on LPS/HIV exposure. Finally, functional validations and meta-analysis comparing the transcriptome of monocyte and MDDC subsets revealed that CD16+ vs CD16− monocytes preserved their superior ability to produce TNF-α and CCL22, as well as other sets of transcripts (eg, TCF4), during differentiation into DC. These results provide evidence that monocyte subsets are transcriptionally imprinted/programmed with specific differentiation fates, with intermediate/nonclassical CD16+ monocytes being precursors for pro-inflammatory CD103+RALDH2+TCF4+ DCs that may play key roles in mucosal immunity homeostasis/pathogenesis. Thus, alterations in the CD16+/CD16− monocyte ratios during pathological conditions may dramatically influence the quality of MDDC-mediated immunity.

Human Dendritic Cell Subsets, Ontogeny, and Impact on HIV Infection

“…DC-like cells can be generated by differentiation of monocytes into monocyte-derived DCs (MDDCs), which can occur in vitro via IL-4 and granulocyte-macrophage colony stimulatory factor (GM-CSF) supplementation or in vivo at tissue sites during inflammation (77–79), but whether MDDCs form in circulation during homeostasis is unclear. CD16 + MDDCs generated in vitro express several key genes associated with the DC4s described by Villani et al (14), namely SERPINA1, CD97, ITGAL , and TCF7L2 (80), but CD14 + MDDCs appear to transcriptionally align with CD14 + DCs in skin rather than CD14 + blood monocytes (50). Further fate mapping and lineage tracing studies adopting the exact gating strategy used to describe these subsets would be valuable for confirming their exact ontogeny.…”

6-Sulfo LacNAc (Slan) as a Marker for Non-classical Monocytes

“…It was shown that CHST2 can link the residue to the PSGL1 protein molecule (5). There are additional transferases including CHST15, which similar to CHST2 shows increased mRNA expression in CD16+ monocytes (12) and B3GALT2, which is increased in slan+ compared to slan- CD16+ monocytes (13). These findings need confirmation and the role of these transferases in generating the slan-residue needs to be determined.…”

HIV-1 is rarely detected in blood and colon myeloid cells during viral-suppressive antiretroviral therapy

“…Similar findings were reported for CD16 + Mo in the context of SIV infection [28] , with increased CD16 + Mo activation being associated with an increased risk of SIV acquisition in the context of a vaccination trial [29] . Finally, CD16 + and CD16 -Mo differentiate into DC and MΦ with unique molecular features that qualify them as key players in HIV pathogenesis [30][31][32] . While it is well-documented that CD16 + Mo fuel chronic inflammation in HIV/SIV infection, their contribution to HIV reservoir persistence during ART remains unclear.…”