Huntington’s disease (HD) is an incurable, autosomal dominant neurodegenerative disease that commonly presents in midlife with a combination of a movement disorder, psychiatric and cognitive problems. The disease is caused by a trinucleotide repeat expansion in exon 1 of the huntingtin gene that translates to an expanded polyglutamine tract in the mutant huntingtin protein (mHTT). Recent clinical and experimental evidence has suggested a pathogenic role of immune activation in HD. In fact, dysfunction of central nervous system and peripheral myeloid cells was found to precede disease onset in human carriers of the gene mutation and in HD animal models. However, the differential roles of resident microglia versus peripherally derived myeloid cells have not been addressed in vivo in HD. We shall specifically express mHTT in microglia or peripheral myeloid cells by crossing RosaHD knock-in mice with Cx3cr1CreER and LysMCre mice, respectively. Cell-autonomous effects of mHTT on microglia and monocyte/macrophage function will be determined by transcriptomic analysis. Non-cell-autonomous effects of myeloid cells on neuronal dysfunction will be assessed by behavioural analysis of the animals, electrophysiological recordings in slices, as well as transcriptomic and neuropathological studies of the brains. In addition, animals will be challenged with lipopolysaccharide injections in order to determine the contribution of sterile inflammation to neuronal damage. As mHTT directly interacts with the nuclear factor-κB pathway, we shall conditionally ablate A20 in myeloid cells and determine the impact on HD pathogenesis. A particular focus of our experiments will be on the intercellular transmission of misfolded mHTT. In order to relate our findings to the human condition, we shall generate microglia-like cells from induced pluripotent stem cells derived from HD patients and controls, which will be tested in neuronal cultures, organotypic brain slices and after corticostriatal transplantation in mice. Together, our experiments will contribute to a better understanding of the role of myeloid cell dysfunction in HD.