Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment

Abstract

In mice, conventional and plasmacytoid dendritic cells (DCs) derive from separate hematopoietic precursors before they migrate to peripheral tissues. Moreover, two classes of conventional DCs (cDC1 and cDC2 DCs) and one class of plasmacytoid DCs (pDCs) have been shown to be transcriptionally and functionally distinct entities. In humans, these three DC subtypes can be identified using the cell surface markers CD1c (cDC2), CD141 (cDC1), and CD303 (pDCs), albeit it remains elusive whether DC functionality is mainly determined by ontogeny or the tissue microenvironment. By phenotypic and transcriptional profiling of these three DC subtypes in different human tissues derived from a large number of human individuals, we demonstrate that DC subpopulations in organs of the lymphohematopoietic system (spleen, thymus, and blood) are strongly defined by ontogeny rather than by signals from the microenvironment. In contrast, DC subsets derived from human lung or skin differed substantially, strongly arguing that DCs react toward modulatory signals from tissue microenvironments. Collectively, the data obtained in this study may serve as a major resource to guide further studies into human DC biology during homeostasis and inflammation.

Human dendritic cell subsets: an update

“…The functional and anatomical classification of DC as ‘migratory tissue DC’ or ‘lymph node resident DC’ remains useful to define context. However, comparative gene expression studies have driven a robust classification of DC based primarily on lineage, that correlates with the differential expression of key transcription factors such as interferon regulatory factors 8 and 4 (IRF8 and IRF4) and performs well across all mammalian species . This recognizes plasmacytoid DC (pDC) and two types of ‘conventional’ or ‘classical’ DC (cDC) corresponding to the two subsets of myeloid DC previously defined by CD141 and CD1c expression in humans .…”

“…The original markers, CD141 and CD1c have limitations as both are induced on cDC and monocyte‐derived cells in tissues and in culture. Expression profiling has now provided a suite of more consistent markers that perform well across species, such as CLEC9A, CADM1, BTLA and CD26 for CD141 + myeloid cDC1, and CD2, Fc ε R1 and SIRPA for CD1c + myeloid cDC2 (Table ). Additional complexity discussed below is the emergence of subsets of cDC2 and the realization that conventional pDC gates include myeloid cDC precursors that also express CD123 and CD303 …”

“…These include the well‐known human pDC markers CD303 (CLEC4C; BDCA‐2), CD304 (neuropilin; BDCA‐4) CD85k (ILT3) and CD85g (ILT7) together with more recently characterized antigens Fc ε R1, BTLA, DR6 (TNFRSF21/CD358) and CD300A . Transciptional profiling has also added the markers FAM129C, CUX2 and GZMB . Several recent papers have described a small subset of CD123 + pDC that express CD2 + , CD56 + or CD5 .…”

“…Other markers should be used for confirmation: CLEC9A, the receptor for actin exposed during cell necrosis, the cell adhesion molecule CADM1 (NECL2) and the antigen BTLA considerably increase the accuracy of identification. Indoleamine 2,3‐dioxygenase is also highly expressed . Lack of expression of monocyte and cDC2 markers such as CD14, CD11b and SIRP α is also important.…”

Dendritic Cells Display Subset and Tissue-Specific Maturation Dynamics over Human Life

“…Human CD141 + and CD1c + cDCs were originally identified in blood (Dzionek et al, 2000), and have been ontogenetically aligned to mouse cDC1 and cDC2, respectively (Bachem et al, 2010; Crozat et al, 2010; Jongbloed et al, 2010; Poulin et al, 2010). Human DC subsets have been characterized in tissues (Guilliams et al, 2016; Haniffa et al, 2012; Heidkamp et al, 2016; Watchmaker et al, 2014), however, tissues were derived from isolated surgical explants from a small number of individuals at different life stages. The ability to adapt DC therapies to the diverse human population requires a comprehensive analysis of DC populations in multiple tissues at different life stages.…”