Control of Lymphocyte Fate, Infection, and Tumor Immunity by TCF-1

T cell factor-1 (TCF-1) acts as a transcription factor and histone deacetylase (HDAC) in both mouse and humans to shape innate and adaptive immunity. Expression of TCF-1 is necessary for the development of ILC progenitor cells in mouse bone marrow. In murine T cell development, TCF-1 is critical for ETP development, commitment to the CD4+ T cell lineage, and stabilization of CD8+ T cells by suppressing alternative fate differentiation. Increased TCF-1 expression is important for the development of central memory CD8+ T cells that provide long-term protection following acute viral infection in mice. TCF-1 is critical for the development of Tex-stem cells that replenish Tex-term cells following chronic viral infection and in response to tumor formation. The presence of Tex-stem cells can be predictive of good prognosis in various cancer types and help to mediate patient responses to ICB. T cell factor-1 (TCF-1), encoded by Tcf7, is a transcription factor and histone deacetylase (HDAC) essential for commitment to both the T cell and the innate lymphoid cell (ILC) lineages in mammals. In this review, we discuss the multifunctional role of TCF-1 in establishing these lineages and the requirement for TCF-1 throughout lineage differentiation and maintenance of lineage stability. We highlight recent reports showing promise for TCF-1 as a novel biomarker to identify recently characterized subsets of exhausted CD8+ T cells that may help to predict patient responses to immune checkpoint blockade (ICB). T cell factor-1 (TCF-1), encoded by Tcf7, is a transcription factor and histone deacetylase (HDAC) essential for commitment to both the T cell and the innate lymphoid cell (ILC) lineages in mammals. In this review, we discuss the multifunctional role of TCF-1 in establishing these lineages and the requirement for TCF-1 throughout lineage differentiation and maintenance of lineage stability. We highlight recent reports showing promise for TCF-1 as a novel biomarker to identify recently characterized subsets of exhausted CD8+ T cells that may help to predict patient responses to immune checkpoint blockade (ICB). T and B lymphocytes are activated on exposure to foreign agents eliciting antigen-specific immunity and providing long-term pathogen-specific immunity. artificially engineered T cells expressing T cell receptors that can kill specific antigen-expressing cells (e.g., in cancer therapy). perforin and granzyme are proteins secreted by, for example, cytotoxic CD8+ T cells; they form pores on target cells (perforin) and allow granzyme entry to induce target cell death. chromatin-modifying enzyme; removes acetyl groups on DNA-embedded histone proteins, rendering DNA less accessible to transcription factors. naturally occurring immune cells that are not specific to particular pathogens; they act as the first line of defense in fighting infection and priming the activation of adaptive immune cells. comprise four subsets and include cytotoxic NK cells, TNF- and IFNγ-producing group 1 ILCs (ILC1), IL-5- and IL-13-producing group 2 ILCs (ILC2), and two group 3 ILC (ILC3) subsets, namely ILC3s and lymphoid tissue inducer (LTi) cells, defined by production of IL-17 and IL-22. transcription factor involved in the activation of Wnt signaling target genes; shares common transcriptional functions with TCF-1. adaptive T or B lymphocytes that have previously experienced an antigen and have the ability to rapidly recognize and differentiate into effector cells to eliminate the same pathogen during a secondary encounter, providing lifelong immunity. expressed by all nucleated cells in the body and presents intracellular antigens to immune cells, particularly CD8+ T cells. expressed by antigen-presenting immune cells and presents extracellular antigens to CD4+ T cells to initiate an immune response. the inner surfaces of the mouth, ears, eyes, nose, throat, tonsil, lung, bronchus, intestine, vagina, uterus, urethra, and anus are covered with a thin layer of mucus that protects these surfaces from exposure to the external environment. CD4+FOXP3+ T cells; known to suppress immunity to maintain immune homeostasis after infection by secreting inhibitory cytokines such as TGF-β, IL-35, and IL-10. Thymic (t)Tregs and nTregs develop as T cells mature in the thymus, while iTregs differentiate from naïve CD4+ T cells in response to stimulation in the periphery. the ability of a T cell to differentiate into multiple subsets with self-renewal capacity. promotes reduced effector T cell function (e.g., decreased inflammatory cytokine production, increased expression of negative regulators such as the inhibitory co-receptors PD-1 and CTLA-4). Exhausted T cells retain some function, allowing them to persist and partially contain chronic infection while limiting excessive tissue destruction. TCF-1−CCR7−KLRG1hiIL-7RloCD8+ T cell subset that homes in peripheral lymphoid organs and exhibits rapid effector function, secretion of inflammatory cytokines, and cytotoxic molecules on stimulation. in chronic infection and cancer, tumor-antigen-experienced CD8+ T cells give rise to CD8+TCF-1+PD-1+TIM3− cells with stem-cell-like properties that can differentiate into Tex-term cells; their differentiation is promoted by blocking PD-1. subset of exhausted CD8+ T cells with low expression of TCF-1; they retain some effector functions, but secrete reduced inflammatory cytokines and cytotoxic molecules compared with Teff cells. CD4+CXCR5+ cells; prime B cells to develop antigen-specific antibody responses in germinal centers; critical for long-term antibody-mediated immunity. CD4+CXCR5+FOXP3+ T cells that inhibit B cell function to maintain immune homeostasis. subset of CD4+T-BET+ T cells; promote cell-mediated immunity by promoting macrophage function and providing help to CD8+ T cells, through secretion of TNF-α and IFNγ. subset of CD4+GATA3+ T cells; secrete IL-4, IL-5, IL-6, IL-10, and IL-13 to stimulate an immune response against helminth infection and extracellular pathogens and promote allergic reactions. CD4+RORγt+ T cells characterized by the secretion of IL-17, inducing neutrophil recruitment and promoting tissue repair and clearance of bacterial and fungal infection. TCF-1+CCR7+KLRG1loIL-7RhiCD8+ T cell subset that homes to secondary lymphoid organs, has self-renewal capacity, and can differentiate into Teff subsets to maintain long-term immunity against antigens. differentiate from naïve CD8+ T cells on antigen exposure, express TCF-1 and CCR7, are KLGR1loIL-7Rhi, and can differentiate into Teff or Tmem cells.