Fig 1: Deletion of TREM2 suppresses the development of disease-associated microglia (DAMs) in vivo.UMAP plots from WT and TREM2 knockout microglia transplanted into a a MITRG or b 5x-MITRG mouse. Top left shows the TREM2 genotype of each cell in the plot (gray = WT, blue = TREM2 KO) and the adjacent UMAP shows the clustering of human microglia sub-populations in non-diseased mice. Pie charts highlight the relative distribution of each TREM2 genotype within each cluster. The lower four UMAP plots demonstrate the relative expression of known homeostatic (green), human leukocyte antigen (HLA, yellow), interferon (pink), and DAM (red) markers. Homeostatic: CX3CR1, P2RY12, P2RY13, TMEM119, SALL1. HLA: HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, HLA-DMA, HLA-DQA1, HLA-DQA2, HLA-DQB1, CD74. Interferon: IFIT1, IFIT2, ISG15, IFI6, IFITM3, MX1, MX2, STAT1. DAM: CD9, TREM2, SPP1, ITGAX, CD83, APOC1, LGALS3. Bar graphs show relative cluster percentages for each cell type. c Flow cytometry of co-transplanted TREM2 WT and KO microglia. Left dot plot shows GFP positive WT microglia (and GFP negative KO microglia) expression of CD9. Middle plot shows the same data as a histogram pre-split on RFP/GFP expression. As in (a), expected % CD9+ cells is around 5–10%. Right plot shows the quantification of all animals n = 6 independent 5x-MITRG mice and 4 MITRG mice. (two way ANOVA with Tukey post hoc test, *p = 0.018; **p = 0.0099, ns p = 0.916). Data are represented as mean values±SEM. Gating strategy in Source data file. d Histological analysis of human microglia within the 5x-MITRG mouse confirms TREM2 WT microglia (RFP+) express higher levels of the activation markers d HLA-DRB1 (gray) and e CD9 than TREM2 knockout microglia (GFP+). Reverse permutation of WT/KO shown in Supplementary Fig. 6. Scale bar low power: 40µm high power: 10µm (n=9 individual mice per genotype with 4 images per mouse. unpaired t-test two-tailed ****p < 0.0001). Transplants were completed with one isogenic set. Data are represented as mean values±SEM.