Estudio del origen y la diferenciación de las células dendríticas inflamatorias durante la infección por Leishmania major

Abstract

This research work is based on previous studies performed in our laboratory, relying on the Leishmania major infection model, that demonstrated for the first time the potential of monocytes to differentiate into dendritic cells in vivo during infectious processes. As a followup of these studies, we have addressed, using the same experimental model, a number of unresolved issues related to the differentiation of dendritic cells, that included - the contribution of monocytes to the generation of the different dendritic cell subsets present in the dermal infection focus and draining lymph nodes, - the origin of the dermal dendritic cells during infectious processes , - the definition of the growth factors controlling the differentiation of these different dendritic cell subsets and - the differentiation of the different macrophage subsets present in the lymph nodes draining the infected skin. For this purpose, a series of experiments have been performed in C57BL/6 mice infected with Leishmania major in the hind footpad in order to - define the phenotype and differentiation kinetics of the different dendritic cell subsets present in the dermis and draining lymph nodes, - determine their level of infection, proliferation status and migration capacity, - explore the potential of monocytes as precursors for these dendritic cell subsets through monocyte intravenous transfer assays and analysis of CCR2-deficient mice, - define the cytokines controlling the differentiation of the different subsets of dendritic cells and macrophages using mice deficient in the receptor for GM-CSF or the receptor Flt3, as well as mice treated with anti-IL-3 or anti-M-CSF-R antibodies. The results derived from this research work have allowed to define the relative contribution of monocytes and pre-DC precursors to the generation of the different dendritic cell subsets present in the dermis and draining lymph nodes of Leishmania major infected mice, the monocytic origin of dermal dendritic cells during infectious processes, as well as the role of the cytokines GM-CSF, M-CSF and Flt3L in the differentiation of the different subsets of dendritic cells and macrophages during Leishmania major infection.