'CL:0000784 (plasmacytoid dendritic cell) should not have synonym 'DC2', 'type 2 DC'

[ANiknejad]

Hello CL Team,

This issue is related to issue #838 , please let me know if I misunderstand something here, thank you very much in advance

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01088/full

Traditionally, the DC population in peripheral blood has been classified into two lineages based on phenotypic and functional characteristics. Conventional DCs (cDCs), also known as myeloid DCs, can be defined as CD11c+ CD123− and are specialized at antigen uptake and presentation to naïve T cells, thus representing the “typical” antigen-presenting DC that primes adaptive immunity. cDCs have previously been subdivided into two subsets (cDC1 and cDC2) based on homology to murine equivalents (CD8α+/CD103+ and CD11b+ DCs respectively) (25) and the differential expression of key transcription factors that drive their development; interferon regulatory factor (IRF)8, basic leucine zipper transcriptional factor ATF-like 3 (BATF3) and DNA-binding protein inhibitor 2 (ID2) for cDC1 and IRF4, Neurogenic locus notch homolog protein 2 (Notch2) and Kruppel-like factor 4 (KLF4) for cDC2 (26, 27). In contrast, plasmacytoid DCs (pDCs) are CD11c− CD123+ cells best characterized for their type I interferon (IFN-I) production during viral infection but can also perform a variety of other functions including T cell stimulation and pro-inflammatory cytokine and chemokine secretion

CL:0000990 name: conventional dendritic cell synonym: "cDC" EXACT [] synonym: "DC1" EXACT []

Why not one specific class for DC1, and one for DC2, both with is_a: CL:0000990 ! conventional dendritic cell (or myeloid dendritic cell, as asked in issue #838?

[addiehl]

As mentioned in my reply to #838, I will review the synonyms for the various DC terms in CL. Anna Maria @masciam may also be able to provide some background.

[addiehl]

I've looked into various synonyms for different types of dendritic cells, and in fact there is a very good basis for the DC1 synonym in CL for 'conventional dendritic cell' (CL:0000990) and DC2 for 'plasmacytoid dendritic cell' (CL:0000784). The DC1 and DC2 nomenclature appears in papers from the late 1990s and early 2000s (PMID:10024247, PMID:10364556, PMID:10517895, PMID:11120774, PMID:12393665, for instance). While this usage is not found anymore in the literature, it is still necessary to represent in the CL.

So we have many synonyms in use for different types of dendritic cells: Conventional dendritic cells: DC1, cDC, cDC1, cDC2, type 1 DC Precursors to conventional dendritic cells: pDC1 Myeloid dendritic cells (a subset of conventional DC): mDC

Plasmacytoid dendritic cells: DC2, pDC, IPC, type 2 DC Precursors to Plasmacytoid dendritic cells: pDC2

So the synonyms DC1 and DC2 are correct as exact synonyms for CL:0000990 and CL:0000784, respectively, and will remain as they are in CL. It is unfortunate that dendritic cells have such mixed up synonyms, but that is how it is.

How to handle cDC1 and cDC2 remains to be determined, but probably cDC1 can be added to 'CD103-positive dendritic cell' (CL:0002461) as at least a broad synonym, and cDC2 can be added to 'CD11b-positive dendritic cell' (CL:0002465) as a broad synonym, because these two cell types are defined by mouse markers and the analogous human DC types are defined with different markers per PMID:31156637 (the Frontiers article cited above). Additional work is needed to ensure we are representing human DC subtypes fully and accurately.

--Alex

[addiehl]

I see that this science paper from 2017 (PMID:28428369) provides even more confusion about the usage of DC1 and DC2. I guess these authors were either unaware of the earlier usage of DC1 and DC2 or chose to ignore it.

[emquardokus]

@addiehl @aleixpuigb Several more recent papers state there are 3 types of dendritic cells; CellHint also lists 3 as DC1, DC2, pDC--right now CL has DC2 as a synonym of pDC, but molecular characterization would suggest 3 distinct. "three major DC subsets: plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2). "Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology. 2018 May;154(1):3-20. doi: 10.1111/imm.12888. Epub 2018 Feb 27. PMID: 29313948; PMCID: PMC5904714." Muzz Hanifa's group (works with Sarah Teichmann and Human Cell Atlas project): Jardine, Laura, and Muzlifah Haniffa. 2020. “Reconstructing Human DC, Monocyte and Macrophage Development in Utero Using Single Cell Technologies.” Molecular Immunology 123 (July): 1–6. https://doi.org/10.1016/j.molimm.2020.04.023. "Recent insights from single cell RNA sequencing (Villani et al., 2017; See et al., 2017) agree with earlier consensus definitions that divide DCs into three major groups: plasmacytoid DCs, myeloid DC1 and DC2. "

CellHint tool and CellTypist also have 3 distinct cell types, but if you try to map to Cell Ontology, now pDC and DC2 are the same cell based on synonym. Xu, Chuan, Martin Prete, Simone Webb, Laura Jardine, Benjamin J. Stewart, Regina Hoo, Peng He, Kerstin B. Meyer, and Sarah A. Teichmann. 2023. “Automatic Cell-Type Harmonization and Integration across Human Cell Atlas Datasets.” Cell 186 (26): 5876-5891.e20. https://doi.org/10.1016/j.cell.2023.11.026.

[aleixpuigb]

The literature describes cDC1 as CD141+ XCR1+ and CLEC9A+, which aligns with CD141-positive myeloid dendritic cell. cDC2 is described as a CD1c+ cell. However, the cell term in CL CD1c-positive myeloid dendritic cell have some markers described in a comment that are not the typical markers used to describe cDC2 cells. Moreover, the exact same markers are in a comment for CD16-positive myeloid dendritic cell, meaning, they are not specific. Looking at the reference provided (PMID:20204387), it is likely that this term is meant to be a conventional DC2 cell (cDC2), but the markers that were added were not specific (except CD1c).

Given that the terminology (classical dendritic cell type 1 and 2, cDC1 and cDC2) is widely used (and requested by many projects), it would be good to rename the cells and maintain the current labels as synonyms.

Supporting bibliography

Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017 Apr 21;356(6335):eaah4573. doi: 10.1126/science.aah4573. PMID: 28428369; PMCID: PMC5775029.

Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology. 2018 May;154(1):3-20. doi: 10.1111/imm.12888. Epub 2018 Feb 27. PMID: 29313948; PMCID: PMC5904714.

Heger L, Hofer TP, Bigley V, de Vries IJM, Dalod M, Dudziak D and Ziegler-Heitbrock L (2020) Subsets of CD1c+ DCs: Dendritic Cell Versus Monocyte Lineage. Front. Immunol. 11:559166. doi: 10.3389/fimmu.2020.559166

Schreibelt G, Tel J, Sliepen KH, Benitez-Ribas D, Figdor CG, Adema GJ, de Vries IJ. Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunol Immunother. 2010 Oct;59(10):1573-82. doi: 10.1007/s00262-010-0833-1. Epub 2010 Mar 5. PMID: 20204387.

[ANiknejad]

hello All, I appreciate your feedbacks, but still wondering (sorry in advance about that!) what are the CL ids for these cell types, finally, considering the last CL version?

Precursors to conventional dendritic cells: pDC1 Precursors to Plasmacytoid dendritic cells: pDC2

[scheuerm]

In the HLCA lung atlas: DC1 skos:relatedMatch conventional dendritic cell (CL:0000990); selectively expressed the combination of CLEC9A and DNASE1L3 transcripts in human lung DC2 skos:relatedMatch CD1c-positive myeloid dendritic cell (CL:0002399); selectively expressed the combination of CLEC10A and HLA-DQA1 transcripts in human lung pDC skos:exactMatch plasmacytoid dendritic cell (CL:0000784); selectively expressed the combination of LILRA4 and JCHAIN transcripts in human lung

In LungMAP CellRef: Classical DC subset 1 skos:relatedMatch conventional dendritic cell (CL:0000990); selectively expressed the combination of CLEC9A and IDO1 transcripts in human lung Classical DC subset 2 skos:relatedMatch CD1c-positive myeloid dendritic cell (CL:0002399); selectively expressed the combination of CLEC10A and PKIB transcripts in human lung Plasmacytoid DC skos:exactMatch plasmacytoid dendritic cell (CL:0000784); selectively expressed the combination of LILRA4 and SCT transcripts in human lung

I would also argue that cDC1 and cDC2 share a myeloid progenitor, whereas pDC is derived from a lymphoid progenitor and may not even be a dendritic cell. The definition of dendritic cell (CL:0000451) is "A cell of hematopoietic origin, typically resident in particular tissues, specialized in the uptake, processing, and transport of antigens to lymph nodes for the purpose of stimulating an immune response via T cell activation. These cells are lineage negative (CD3-negative, CD19-negative, CD34-negative, and CD56-negative)." I am not sure that pDCs traffic to lymph nodes and I'd be surprised if they have dendrites.