Ly6D+ Siglec-H+ precursor cells contribute to conventional dendritic cells via a Siglec-H+ Zbtb46+ Ly6D+ intermediary stage

Lutz, Konstantin Josef (2023): Ly6D+ Siglec-H+ precursor cells contribute to conventional dendritic cells via a Siglec-H+ Zbtb46+ Ly6D+ intermediary stage. Dissertation, LMU München: Medizinische Fakultät

Abstract

Dendritic cells (DC) are antigen-presenting cells that form an indispensable part of the immune system. While conventional/classical dendritic cells (cDC) are largely involved in orchestrating T cell responses to extracellular pathogens and in anti-tumor immune responses, plasmacytoid dendritic cells (pDC) are the main driver of anti-viral defense through production of large amounts of type I interferons in response to viral infection. The origin and differentiation of these functionally distinct pDC and cDC has been studied extensively in the past decades, but the respective DC ontogeny is still subject to debate. In this study the CD11c+ Siglec-H+ CCR9low DC precursor fraction in murine bone marrow (BM) was studied in detail to unravel the heterogeneity of cells within this compartment and their commitment to cDC and/or alternative pDC fate. In steady state conditions, CD11c+ Siglec-H+ Ly6D+ Zbtb46- CCR9low B220high cells had almost exclusive pDC potential, while CCR9low B220low cells gave rise to pDC as well as cDC in vitro and after adoptive transfer in vivo. I further demonstrated that stimulating these cells with TLR9 agonists and type I interferons increased pDC output while limiting cDC output in vitro by driving pDC maturation and at the same time impeding pre-cDC proliferation and terminal differentiation. Data from single-cell RNA-sequencing of DC related cell populations and multiparameter spectral flow cytometry of steady-state BM and splenic cells of Zbtb46wt/ki mice were analyzed using powerful bioinformatic tools, leading to the discovery of a cDC-committed CD11c+ Siglec-H+ Zbtb46+ Ly6D+ precursor cell population that bridges the gap between CD11c+ Siglec-H+ Ly6D+ lymphoid-derived pDC-biased precursors and pre-cDCs. In vitro and in vivo differentiation assays further showed that cells with this phenotype mark a transitional state between advanced CD11c+ Siglec-H+ CCR9low lymphoid precursors and mature cDCs. The contribution of lymphoid precursors to cDCs may be relevant when cDCs are depleted and their regeneration from myeloid progenitor cells is impaired, such as during severe infections.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 29. Juni 2023
• 1. Bericht­erstatter:in: Krug, Anne