Abstract
The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/β-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.
Highlights
T cell factor 1 (TCF1, encoded by TCF7) was discovered in studies aiming at identifying regulators of human T lymphocyte development [1]
Our preliminary studies show that naïve CD4 T cells from older individuals have reduced TCF1 expression compared to young adults (Ye et al, submitted) (Figure 2)
TCF1 controls common gene-regulatory networks governing the generation of T follicular helper (TFH) cells, memory precursor cells and stem-like CD8 T cells
Summary
T cell factor 1 (TCF1, encoded by TCF7) was discovered in studies aiming at identifying regulators of human T lymphocyte development [1]. TCF1 was discovered in 1996 to function as a direct effector downstream of the WNT/β-catenin signaling pathway [8] that plays essential roles in embryonic development [9] and stem cell self-renewal in adult tissues [10]. WNT signaling is initiated by the binding of an extracellular WNT-protein ligand to a cell surface Frizzled family receptor. This binding induces an intracellular signaling cascade that prevents GSK-3β-mediated β-catenin phosphorylation and proteasomal degradation, allowing β-catenin to accumulate in the cytoplasm and translocate into the nucleus. WNT signaling as well as TCF1-regulated expression of transcription factors and T cell identity genes play a role in the differentiation of mature T cells. We will review recent insights into the mechanisms of how TCF1 regulates T cell fate in response to acute and chronic infections and discuss the implications of TCF1 function for T cell exhaustion and T cell aging
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