Abstract
Monocytes are haematopoietic stem cell-derived, immune effector cells. In mice, monocytes consist of two principal subsets: the classical Ly6C-expressing subset and the patrolling Ly6Clow subset. The origin and fate of Ly6Clow monocytes remains a topic of debate, as does their interrelationship with Ly6C+ monocytes. The current model of Ly6Clow monocyte development suggests that Ly6C+ monocytes are the obligate, steady state precursors of the Ly6Clow subset, undergoing conversion or maturation within the blood. However, several studies have reported differing genetic dependencies of monocyte subsets that are in conflict with this model of Ly6Clow monocyte development.To re-investigate monocyte precursor-product relationships, this project combined genetic, kinetic and adoptive transfer studies to probe the interrelationships between bone marrow precursors, blood monocytes and tissue macrophages. This study firstly confirms the existence of a third, minor monocyte subset that expresses MHC II and varying levels of Ly6C and is found in the blood, spleen and bone marrow monocyte compartments. Secondly, this study establishes that all three monocyte subsets arise in the bone marrow from a proliferating common pro-monocyte via two genetically distinct lineages. This study demonstrates that Ly6Clow MHC II- monocytes arise from a novel Nr4a1-dependent, Irf8-independent intermediate population in the bone marrow compartment under steady state conditions, whereas. Thirdly, Nr4a1-dependent monocytes have a long half-life and circulate within the systemic and splenic vasculature, contributing minimally to tissue macrophage populations under steady state conditions. The findings in this thesis clarify and extend our understanding of monocyte genetic and functional heterogeneity.
| Date of Award | 2016 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Frederic Geissmann (Supervisor) |