MLL1-COMPASS establishes developmental patterning of the memory CD8 T cell compartment and ensures regenerative immunity.

Abstract CD8+ T cells with stem cell-like qualities (TSTEM) provide central memory following resolved intracellular infections, and serve as progenitor cells that sustain effector-like cell development during chronic infections and tumors, both naturally and in response to immunotherapeutic PD-1 blockade. However, the chromatin regulatory factors (CRFs) and transcriptional programs that establish TSTEM cell differentiation are unclear. Using an RNA interference screen of all CRFs we discovered that Mixed Lineage Leukemia 1 (MLL1) was required in activated CD8 T cells to promote Id3-GFP reporter expression and to coordinately restrain PD-1, LAG3 and TIM3 expression. Single cell RNA-seq analysis demonstrated Kmt2a (MLL1) was preferentially expressed in P14 CD8 T cells enriched with TSTEM gene expression during lymphocytic choriomeningitis virus (LCMV) infection. P14 CD8 T cells depleted of MLL1 failed to establish TSTEM-like cells, terminally differentiated prematurely, failed to sustain responses to chronic LCMV infection and tumors, and failed to develop central memory subsets during acute LCMV infection. MLL1 preferentially bound transcriptional start sites (TSSs) in CD8 T cells, and was essential for global accumulation of H3K4me3, H4K16ac, and RNA Polymerase II CTD-phosphorylation during TCR stimulation. These results suggest that MLL1-COMPASS organizes TSS activity to establish transcriptional programs that delineate TSTEM and terminal differentiation.