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bioRxiv · 10.64898/2026.04.03.715913

The MLL1-MENIN complex preserves CD8 T cell memory through a TOX-BTLA-TCF1 axis

Chiu, B. C.
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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.

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Chiu, B. C.. 2026-04-06. The MLL1-MENIN complex preserves CD8 T cell memory through a TOX-BTLA-TCF1 axis. https://doi.org/10.64898/2026.04.03.715913

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