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

被引:18
作者
Wacleche, Vanessa Sue [1 ,2 ]
Cattin, Amelie [1 ,2 ]
Goulet, Jean-Philippe [3 ]
Gauchat, Dominique [2 ]
Gosselin, Annie [2 ]
Cleret-Buhot, Aurelie [2 ]
Zhang, Yuwei [1 ,2 ]
Tremblay, Cecile L. [1 ,2 ]
Routy, Jean-Pierre [4 ,5 ]
Ancuta, Petronela [1 ,2 ]
机构
[1] Univ Montreal, Fac Med, Dept Microbiol Infect & Immunol, Montreal, PQ, Canada
[2] CHU Montreal, Ctr Hosp, Montreal, PQ, Canada
[3] Caprion Biosci Inc, Montreal, PQ, Canada
[4] McGill Univ, Chron Viral Illness Serv & Res Inst, Hlth Ctr, Montreal, PQ, Canada
[5] McGill Univ, Div Hematol, Hlth Ctr, Montreal, PQ, Canada
基金
加拿大健康研究院;
关键词
CD4(+) T-CELLS; RETINOIC ACID; CD16-POSITIVE MONOCYTES; BLOOD MONOCYTES; IMMUNODEFICIENCY-VIRUS; EXPRESSION PROFILES; 6-SULFO LACNAC; STEADY-STATE; BETA-CATENIN; MACROPHAGES;
D O I
10.1182/bloodadvances.2018020123
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-alpha 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.
引用
收藏
页码:2862 / 2878
页数:17
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