The MLL1–MENIN complex preserves CD8 T cell memory through a TOX–BTLA-TCF1 axis
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Immunological memory depends on the maintenance of stem cell-like memory CD8 T cells, which require sustained expression of the transcription factors TCF1. Here, I identify MLL1 as a key regulator of CD8 T cell memory. In activated T cells, MLL1 sustains Tox transcription through interaction with MENIN, thereby maintaining BTLA expression and restraining cytokine-driven AKT activation. Loss of MLL1 or disruption of the MLL1–MENIN interaction accelerates AKT-driven loss of TCF1, leading to impaired memory potential. MLL1-deficient T cells fail to reconstitute lymphopenic hosts and are unable to mediate graft-versus-host disease, while exhibiting increased expansion of virtual memory T cells. Unexpectedly, MLL1 regulates Tox, Btla and Tcf7 independently of its methyltransferase activity and MOF-mediated H4K16 acetylation. These findings define a pathway in which the MLL1–MENIN complex restrains cytokine signaling to preserve CD8 T cell memory and identify a noncanonical function of MLL1 in transcriptional maintenance.
