Circulating IRF8-expressing CD123+CD127+ lymphoid progenitors: key players in human hematopoiesis

Abstract

Lymphopoiesis is the process in which B and T cells, and innate lymphoid cells (ILCs) develop from hematopoietic progenitors that exhibit early lymphoid priming. The branching points where lymphoid-primed human progenitors are further specified to B/T/ILC differentiation trajectories remain unclear. Here, we discuss the emerging role of interferon regulatory factor (IRF)8 as a key factor to bridge human lymphoid and dendritic cell (DC) differentiation, and the current evidence for the existence of circulating and tissue-resident CD123⁺CD127⁺ lymphoid progenitors. We propose a model whereby DC/B/T/ILC lineage programs in circulating CD123⁺CD127⁺ lymphoid progenitors are expressed in balance. Upon tissue seeding, the tissue microenvironment tilts this molecular balance towards a specific lineage, thereby determining in vivo lineage fates. Finally, we discuss the translational implication of these lymphoid precursors.

Keywords: IRF8; hematopoiesis; hematopoietic tissues; human; lineage cell fate; lymphoid progenitor cells.

Figure 1. Circulating CD123⁺CD127⁺ lymphoid progenitors sustain human ILC and T cell development.

In this model of hematopoiesis, CD123⁺CD127⁺ lymphoid progenitors in the peripheral blood express IRF8 and are DC- and lymphoid-primed. Additional signals from the tissue microenvironment are likely to enforce specific lineage programs in these lymphoid progenitors and lead to lineage segregation that establish their in vivo cell fates. Recent studies indicate that circulating CD123⁺CD127⁺ lymphoid progenitors give rise to fetal innate lymphoid cell lineage-specified progenitors [18], as well as to fetal [26] and postnatal [13, 14] thymus seeding progenitors upon tissue seeding. These tissue-resident progenies of circulating CD123⁺CD127⁺ lymphoid progenitors have increased expression of IRF8 and CD123. Some elements in this figure were created using BioRender.com.

Figure 2. scRNA-sequencing studies clarify the expression of IRF8 in human HSPCs.

For illustrative purposes, previous published data were compiled and presented as: (A) A Uniform Manifold Approximation and Projection (UMAP) of adult CD19-CD34⁺ HSPCs isolated from bone marrow (BM), steady state peripheral blood (PB) and G-CSF mobilized PB [32]. (B) Expression of IRF8 in (A). (C) UMAP of adult CD19^-CD34⁺ HSPCs isolated from spleen [32]. (D) Expression of IRF8 in (C). (E) UMAP of CD34⁺ HSPCs isolated from fetal liver, fetal BM, and cord blood [37]. (F) Expression of IRF8 in (E). HSC/MPP, hematopoietic stem cell/multipotent progenitor; MEMBP, megakaryocyte/erythroid/mast cell/basophil progenitor; MyP, myeloid progenitor; EryP, erythroid progenitor; MDP, monocyte/dendritic cell progenitor; LyP, lymphoid progenitor; ND, not defined cluster; MEP, megakaryocyte/erythroid progenitor; EoBasoMC, eosinophil/basophil/mast cell progenitor; CLP, common lymphoid progenitor; DC, dendritic cell. (A-D) were generated from a publicly accessible ShinyCell web app [85]http://bioinf.stemcells.cam.ac.uk:3838/laurenti/mobPB_HSPCs/ and http://bioinf.stemcells.cam.ac.uk:3838/laurenti/ExtramedHSPCs/. (E,F) were generated by Tom Putteman based on the CITE-seq dataset from [37].

Figure 3. Single-cell profiling of human HSPCs supports the existence of circulating adult CD123^-/loCD127⁺ lymphoid progenitors.

For illustrative purposes, previously published data on single-cell profiling of human HSPCs [32] were compiled and presented as: (A) Relative number of the three clusters of lymphoid progenitors (LyP1-3) in each adult tissue. (B) Bubble plot illustrates the relative expression of genes that are associated with myeloid, DC and lymphoid lineages. (C) Bubble plot illustrates the relative expression of cell surface markers that are associated with hematopoietic stem cells/multipotent progenitors (HSC/MPP) and LyP. BM, bone marrow; PB, peripheral blood; MDP, monocyte/dendritic cell progenitor. (A) was generated based on the normalized cell counts from the Supplemental File 5 of [32]. (B) was generated from ShinyCell web app http://bioinf.stemcells.cam.ac.uk:3838/laurenti/mobPB_HSPCs/. (C) was generated by Ahmed Waraky based on the CITE-seq dataset from [32].

Figure 4. Single-cell profiling of human HSPCs supports the existence of fetal CD123^-/loCD127⁺ lymphoid progenitors.

For illustrative purposes, previously published data of single-cell profiling of human HSPCs [37] were compiled and presented (A) Bubble plot illustrates the relative expression of genes that are associated with myeloid, DC, and lymphoid lineages in selected clusters of fetal HSPCs. (B) Bubble plot illustrates the relative expression of cell surface markers that are associated with hematopoietic stem cells/multipotent progenitors (HSC/MPP) and lymphoid progenitors (LyP). CLP, common lymphoid progenitor; DC, dendritic cell. (A,B) were generated by Tom Putteman based on the CITE-seq dataset from [37].

Figure 5. Single-cell profiling of human postnatal immature thymocytes and adult splenic HSPCs suggests the existence of tissue-seeding CD123⁺CD127⁺ lymphoid progenitors.

For illustrative purposes, previously published data of single-cell profiling of human postnatal immature thymocytes [13] and adult splenic HSPCs [32] were compiled and presented as: (A) the schematic illustrates the developmental relationship between thymus seeding progenitor (TSP) subset 1, TSP2, early T cell progenitor (ETP) and IRF8^hi-expressing granulocyte/macrophage progenitors (GMP). (B) Bubble plot illustrates the relative expression of genes that are associated with myeloid, DC, and lymphoid lineages in (A). (C) The relative number of the three clusters of lymphoid progenitors (LyP1-3) in adult spleen are shown. (D) Bubble plot illustrates the relative expression of genes associated with myeloid, DC, and lymphoid lineages in selected clusters from adult splenic HSPCs. (E) Bubble plot illustrates the relative expression of cell surface markers associated with hematopoietic stem cells/multipotent progenitors (HSC/MPP) and LyP. MDP, monocyte/dendritic cell progenitor. (B) was generated by Tom Putteman based on the scRNA-seq dataset from [13]. (C) was generated based on the normalized cell counts from the Supplemental File 5 of [32]. (D) was generated by Hugo P. Bastos based on the scRNA-seq dataset from [32]. (E) was generated by Ahmed Waraky based on the CITE-seq dataset from [32].