The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes

Abstract

The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.

Transcriptional control of natural killer cell differentiation

“…First, TCF-1-deficient mNK cells express lower levels of the inhibitory NK receptor Ly49A and higher levels of CD11b and KLRG1, a phenotype typically associated with terminal maturity. 8,32,33 In addition, TCF-1-deficient NK cells express elevated levels of granzymes, consistent with the finding that TCF-1 binds and promotes a closed chromatin configuration at regulatory elements near the Gzmb gene. Modulation of granzyme expression by TCF-1 may protect developing NK cells from apoptosis, as both TCF-1-deficiency and granzyme overexpression impair the survival of developing NK cells.…”

“…Although TCF‐1 is highly expressed in early developing and immature NK cells, its expression wanes in mNK cells and several lines of evidence suggest that TCF‐1 may actually antagonize later stages of mNK cell maturation. First, TCF‐1‐deficient mNK cells express lower levels of the inhibitory NK receptor Ly49A and higher levels of CD11b and KLRG1, a phenotype typically associated with terminal maturity . In addition, TCF‐1‐deficient NK cells express elevated levels of granzymes, consistent with the finding that TCF‐1 binds and promotes a closed chromatin configuration at regulatory elements near the Gzmb gene.…”

“…In addition, TCF‐1‐deficient NK cells express elevated levels of granzymes, consistent with the finding that TCF‐1 binds and promotes a closed chromatin configuration at regulatory elements near the Gzmb gene. Modulation of granzyme expression by TCF‐1 may protect developing NK cells from apoptosis, as both TCF‐1‐deficiency and granzyme overexpression impair the survival of developing NK cells …”

“…Recent studies have harnessed the power of high‐throughput sequencing platforms to define the global changes in transcription and chromatin accessibility that occur in Ly49H + NK cells during the course of MCMV infection. A key finding of these studies was that memory NK cells and memory CD8 + T cells share a common transcriptional and epigenetic signature, and many of the regulated genes such as Tcf7 , Zeb2 , and Tox have known roles in NK cell development . Moreover, open chromatin regions in memory cells were enriched for binding sites for AP‐1 and underrepresented for TCF‐LEF binding sites, presenting novel pathways that may be involved in memory NK cell formation and/or maintenance …”

Epigenetic control of innate and adaptive immune memory

“…Both TCF1 and LEF1 are often implicated in orchestrating lineage commitment of T cells during development and infection 28 , 36–38 , as well as in various roles during innate lymphocyte development, including NK cells 39 , 40 . Furthermore, TCF1 is a known regulator of the chromatin landscape 38,41 .…”