T Cell Factor 1 Represses CD8+ Effector T Cell Formation and Function

Abstract

The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8+ T cells. However, its role in the initial phases of CD8+ T effector cell formation has remained unexplored. We report that high levels of Wnt signaling and Tcf1 are operational in naive and memory CD8+ T cells, whereas Wnt signaling and Tcf1 were low in effector CD8+ T cells. CD8+ T cells deficient in Tcf1 produce IFN-γ more rapidly, coinciding with increased demethylation of the IFN-γ enhancer and higher expression of the transcription factors Tbet and Blimp1. Moreover, virus-specific Tcf1−/− CD8+ T cells show accelerated expansion in acute infection, which is associated with increased IFN-γ and TNF production and lower viral load. Genetic complementation experiments with various Tcf1 isoforms indicate that Tcf1 dosage and protein stability are critical in suppressing IFN-γ production. Isoforms lacking the β-catenin binding domain are equally effective in inhibiting CD8+ effector T cell formation. Thus, Tcf1 functions as a repressor of CD8+ effector T cell formation in a β-catenin/Wnt-independent manner.

De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+T-cell fate decisions following activation

“…Tcf7, which encodes the Tcf1 protein, has high expression in naïve CD8 + T cells and drops quickly following activation, resulting in low Tcf1 expression in CD127 − KLRG1 + terminal effector cells (29,30). Memory T cells regain high expression of Tcf1, similar to naïve T cells (11). Furthermore, T cells lacking all Tcf1 expression are impaired in memory T-cell differentiation (11,31,32).…”

“…Memory T cells regain high expression of Tcf1, similar to naïve T cells (11). Furthermore, T cells lacking all Tcf1 expression are impaired in memory T-cell differentiation (11,31,32). Based on our MBD-seq results (Fig.…”

“…Several factors have been identified that influence the differentiation and polarization of early effector cells toward either terminal effector cells or memory precursor cells. The initial CD8 + T-cell clonal frequency (5,6), inflammatory signals driving transcription factor expression (2, 7), cytokine stimulation (8,9), and transcription factor expression levels (10,11) all impact the fate of early effector CD8 + T cells. As these T cells are genetically identical, cellular processes of epigenetic regulation would also be predicted to play a key role in determining and perpetuating the fate decisions of individual CD8 + T cells.…”

The Quantity of Autocrine IL-2 Governs the Expansion Potential of CD8+ T Cells

“…Transduction of peripheral murine T cells was performed as described (20) with a few modifications. Single-cell suspensions were prepared from spleens of CD45.1 + OT-I TCR transgenic mice by mincing the tissue through a 70-mm cell strainer, after which cell suspensions were enriched for CD8 + T cells using CD8 + T cell isolation kits II from Miltenyi Biotec.…”

Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

“…The limitation of low natural frequencies can be bypassed by targeting the Wnt/β-catenin pathway in naive cells that results in arrested Teff differentiation and promotion of memory-like CD8 + T cells with Tscm features. Although targeting the Wnt signaling pathway appears to be an effective method to promote stemness and inhibit differentiation, this may restrict the proliferation and function; hence, further research is required for its suitability to improve ACT (62). An alternative method to generate sufficient Tscm is a procedure whereby human naive T cells are activated by CD3/CD28 engagement and culturing in the presence of IL-7, IL-15, and IL-21 (63, 64).…”