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In exploring persistent infections and malignancies, a distinctive subgroup of CD8+ T cells, progenitor exhausted CD8+ T (Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8+ T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors. [ABSTRACT FROM AUTHOR]

Background: Epigenetic remodeling at effector gene loci has been reported to be critical in regulating T cell differentiation and function. However, efforts to investigate underlying epigenetic mechanisms that control T cell behaviors have been largely hindered by very limited experimental tools, especially in humans. Results: In this study, we employed a flow cytometric assay to analyze histone acetylation at single-cell level in human T cells. The data showed that histone acetylation was increased during T cell activation. Among T cell subsets, terminally differentiated effector memory T (TEMRA) cells robustly producing effector cytokines were hyper-acetylated. Conversely, these TEMRA cells had lower expression levels of TCF-1, a key transcription factor for maintaining stem cell features. Pharmaceutical inhibition of histone acetylation using a small molecule C646 restrained the production of effector molecules, but retained stem cell-like properties in T cells after expansion. Conclusions: Per-cell histone acetylation is associated with terminal differentiation and poor stemness in human T cells. These observations suggest a new approach to enhance the stem cell-like properties of T cells and improve the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during anti-tumor responses. Our data showed that the loss of TCF-1 in CD8 T cells also leads to loss of key stimulatory molecules such as CD28. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet. Using both in vitro and in vivo models, we uncovered how TCF-1 regulates critical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches suggested that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulated several critical aspects of T cell function during CD8 T cell response to cancer. Summary Figure: TCF-1 is required for persistent function of CD8 T cells but dispensable for anti-tumor response. Here, we have utilized a novel mouse model that lacks TCF-1 specifically on CD8 T cells for an allogeneic transplant model. We uncovered a molecular mechanism of how TCF-1 regulates key signaling pathways at both transcriptomic and protein levels. These key molecules included LCK, LAT, ITK, PLC-γ1, p65, ERK I/II, and JAK/STAT signaling. Next, we showed that the lack of TCF-1 impacted phenotype, proinflammatory cytokine production, chemokine expression, and T cell activation. We provided clinical evidence for how these changes impact GVHD target organs (skin, small intestine, and liver). Finally, we provided evidence that TCF-1 regulates NKG2D expression on mouse naïve and activated CD8 T cells. We have shown that CD8 T cells from TCF-1 cKO mice mediate cytolytic functions via NKG2D. [ABSTRACT FROM AUTHOR]

Regulatory T cells are suppressive immune cells used in various clinical and therapeutic applications. Canonical regulatory T cells express CD4, FOXP3, and CD25, which are considered definitive markers of their regulatory T-cell status when expressed together. However, a subset of noncanonical regulatory T cells expressing only CD4 and FOXP3 have recently been described in some infection contexts. Using a unique mouse model for the first time demonstrated that the TCF-1 regulation of regulatory T-cell suppressive function is not limited to the thymus during development. Our data showed that TCF-1 also regulated regulatory T cells' suppressive ability in secondary organs and graft-vs-host disease target organs as well as upregulating noncanonical regulatory T cells. Our data demonstrated that TCF-1 regulates the suppressive function of regulatory T cells through critical molecules like GITR and PD-1, specifically by means of noncanonical regulatory T cells. Our in vitro approaches show that TCF-1 regulates the regulatory T-cell effector-phenotype and the molecules critical for regulatory T-cell migration to the site of inflammation. Using in vivo models, we show that both canonical and noncanonical regulatory T cells from TCF-1 cKO mice have a superior suppressive function, as shown by their ability to control conventional T-cell proliferation, avert acute graft-vs-host disease, and limit tissue damage. Thus, for the first time, we provide evidence that TCF-1 negatively regulates the suppressive ability of canonical and noncanonical regulatory T cells. These findings provide evidence that TCF-1 is a novel target for developing strategies to treat alloimmune disorders. [ABSTRACT FROM AUTHOR]

CD4+ T cells are typically considered as 'helper' or 'regulatory' populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4+ cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4+ CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4+ CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4+ CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4+ CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of Tcf7, which encodes TCF-1, at the time of CD4+ T cell activation, we further show that, contrary to observations in CD8+ T cells, continued expression of TCF-1 is not required for CD4+ T cell memory survival. Whilst Tcf7-deficient CD4+ T cells persisted normally following retroviral infection, the CD4+ CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4+ CTL survival. Using xenotransplantation of human CD4+ T cells into murine recipients, we demonstrate that human CD4+ CTLs develop and persist in the same experimental conditions where murine CD4+ CTLs fail to persist. These observations uncover a species-specific defect in murine CD4+ CTL persistence with implications for their use as a model system. [ABSTRACT FROM AUTHOR]

Liver X receptor (LXR) is a critical regulator of cholesterol homeostasis that inhibits T cell receptor (TCR)-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation remain unclear. Here, we demonstrate that LXR is a crucial negative regulator of follicular helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXRβdeficient CD4+ T cell population in response to immunization and lymphocytic choriomeningitis mammarenavirus (LCMV) infection. Mechanistically, LXRβ-deficient Tfh cells express augmented levels of T cell factor 1 (TCF-1) but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with those of LXRβ-sufficient Tfh cells. Loss of LXRβ confers inactivation of GSK3β induced by either AKT/Extracellular signal-regulated kinase (ERK) activation or Wnt/β-catenin pathway, leading to elevated TCF-1 expression in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a cell-intrinsic regulatory function of LXR in Tfh cell differentiation via the GSK3β-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases. [ABSTRACT FROM AUTHOR]

During chronic antigen exposure, a subset of exhausted CD8+ T cells differentiate into stem cell-like or progenitor-like T cells expressing both transcription factor Tcf-1 (T cell factor-1) and co-inhibitory receptor PD-1. These Tcf-1+ stem-like or progenitor exhausted T cells represent the key target for immunotherapies. Deeper understanding of the biology of Tcf-1+PD-1+ CD8+ T cells will lead to rational design of future immunotherapies. Here, we summarize recent findings about the migratory and resident behavior of Tcf-1+ T cells. Specifically, we will focus on TGF-b-dependent lymphoid tissue residency program of Tcf-1+ T cells, which may represent a key to understanding the differentiation and maintenance of Tcf-1+ stem-like CD8+ T cells during persistent antigen stimulation. [ABSTRACT FROM AUTHOR]

Background: T-cell longevity is undermined by antigen-driven differentiation programs that render cells prone to attrition through several mechanisms. CD8 + T cells that express the Tcf-1 transcription factor have undergone limited differentiation and exhibit stem-cell-like replenishment functions that facilitate persistence. We engineered human CD8 + T cells to constitutively express Tcf-1 and a TCR specific for the NY-ESO-1 cancer-associated antigen. Co-engineered cells were assessed for their potential for adoptive cellular immunotherapy. Methods: Tcf-1 mRNA encoding TCF-1B and TCF-1E isoforms, along with GzmB expression were assessed in CD62L + CD57 −, CD62L − CD57 −, and CD62L − CD57 + CD8 + T cells derived from normal donor lymphocytes. The impact of stable Tcf-1B expression on CD8 + T-cell phenotype, anti-tumor activity, and cell-cycle activity was assessed in vitro and in an in vivo tumor xenograft model. Results: TCF-1B and TCF-1E were dynamically regulated during self-renewal, with progeny of recently activated naïve T cells more enriched for TCF-1B mRNA. Constitutive TCF-1B expression improved the survival of TCR-engineered CD8 + T cells upon engagement with tumor cells. Tcf-1B prohibited the acquisition of a GzmB High state, and protected T cells from apoptosis associated with elicitation of effector function, and promoted stem cell-like characteristics. Conclusions: Tcf-1 protects TCR-engineered CD8 + T cells from activation induced cell death by restricting GzmB expression. Our study presents constitutive Tcf-1B expression as a potential means to impart therapeutic T cells with attributes of persistence for durable anti-tumor activity. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Here we show that leukemias induced by aberrant activation of ß-catenin in thymocytes, which bear recurrent Tcra/Myc-Pvt1 translocations, depend on Tcf-1. The DNA double strand breaks (DSBs) in the Tcra site of the translocation are Rag-generated, whereas the Myc-Pvt1 DSBs are not. Aberrantly activated ß-catenin redirects Tcf-1 binding to novel DNA sites to alter chromatin accessibility and down-regulate genome-stability pathways. Impaired homologous recombination (HR) DNA repair and replication checkpoints lead to retention of DSBs that promote translocations and transformation of double-positive (DP) thymocytes. The resulting lymphomas, which resemble human T cell acute lymphoblastic leukemia (T-ALL), are sensitive to PARP inhibitors (PARPis). Our findings indicate that aberrant ß-catenin signaling contributes to translocations in thymocytes by guiding Tcf-1 to promote the generation and retention of replication-induced DSBs allowing their coexistence with Rag-generated DSBs. Thus, PARPis could offer therapeutic options in hematologic malignancies with activeWnt/ß-catenin signaling. [ABSTRACT FROM AUTHOR]

Exhausted CD8+ T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional and epigenetic programs, Tex cells are heterogeneous. Among these, a self-renewing TCF-1+ Tex population, having unique characteristics and the ability to respond to immune-checkpoint blockade, gives rise to TCF-1-terminally Tex cells. These TCF-1+ cells have stem cell-like properties similar to memory T cell populations, but the signals that regulate the developmental pathways and relationships among exhausted cell populations are still unclear. Here, we review our current understanding of Tex cell biology, and discuss some less appreciated molecules and pathways affecting T cell exhaustion. We highlight two co-stimulatory receptors, CD226 and CD137, and their role in inducing or restraining T cell exhaustion, as well as signaling pathways that may be amenable to pharmacological inhibition with a focus on Phosphoinositide-3 Kinase and IL-2 partial agonists. Finally, we discuss novel methods that may increase TCF-1+ populations and therefore improve immunotherapy responsiveness. Understanding features of and pathways to exhaustion has important implications for the success of immunotherapy, including checkpoint blockade and adoptive T-cell transfer therapies. [ABSTRACT FROM AUTHOR]

The immunocytokine PD1-IL2v was designed to overcome liabilities and improve efficacy of IL-2 therapies. PD1-IL2v preferentially targets PD-1+ T-cells and acts on antigen-specific stem-like PD-1+ TCF-1+ CD8+ T-cells expanding and differentiating them towards better effectors resulting in superior efficacy in LCMV chronic infection and tumor models compared to checkpoint inhibition. [ABSTRACT FROM AUTHOR]

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (T pex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy. [Display omitted] • L. johnsonii enhances ICB efficacy via CD8+ T cells • L. johnsonii cooperates with C. sporogenes to produce IPA • IPA activates progenitor exhausted CD8+ T cells by H3K27 acetylation modification • IPA improves ICB responsiveness at the pan-cancer level L. johnsonii and C. sporogenes collaborate to produce indole-3-propionic acid, which modulates CD8+ T cell stemness by increasing H3K27 acetylation at the Tcf7 super-enhancer, thereby enhancing the anti-tumor effect of immune checkpoint blockade in pan-cancer. [ABSTRACT FROM AUTHOR]

The inhibitory receptor TIGIT, as well as theectonucleotidases CD39 and CD73 constitute potential exhaustion markers for T cells. Detailed analysis of these markers can shed light into dysregulation of the T-cell response in acute myeloid leukemia (AML) and will help to identify potential therapeutic targets. The phenotype and expression of transcription factors was assessed on different T-cell populations derived from peripheral blood (PB, n = 38) and bone marrow (BM, n = 43). PB and BM from patients with AML diagnosis, in remission and at relapse were compared with PB from healthy volunteers (HD) (n = 12) using multiparameter flow cytometry. An increased frequency of terminally differentiated (CD45R−CCR7−)CD8+ T cells was detected in PB and BM regardless of the disease state. Moreover, we detected an increased frequency of two distinct T-cell populations characterized by the co-expression of PD-1 or CD39 on TIGIT+CD73−CD8+ T cells in newly diagnosed and relapsed AML in comparison to HDs. In contrast to the PD-1+TIGIT+CD73−CD8+ T-cell population, the frequency of CD39+TIGIT+CD73−CD8+ T cells was normalized in remission. PD-1+- and CD39+TIGIT+CD73−CD8+ T cells exhibited additional features of exhaustion by decreased expression of CD127 and TCF-1 and increased intracellular expression of the transcription factor TOX. CD8+ T cells in AML exhibit a key signature of two subpopulations, PD-1+TOX+TIGIT+CD73−CD8+- and CD39+TOX+TIGIT+CD73−CD8+ T cells that were increased at different stages of the disease. These results provide a rationale to analyze TIGIT blockade in combination with inhibition of the purinergic signaling and depletion of TOX to improve T-cell mediated cytotoxicity in AML. Abbreviations: AML: Acute myeloid leukemia; pAML: newly diagnosed AML; rAML: relapse AML; lrAML: AML in remission; HD: healthy donor; PB: peripheral blood; BM: bone marrow; TIGIT: T-cell immunoreceptor with Ig and ITIM domains; PD-1: Programmed cell death protein 1; CD73: ecto-5′-nucleotidase; CD39: ectonucleoside triphosphate diphosphohydrolase 1; ATP: adenosine triphosphate; ADO: adenosine; CD127: interleukin-7 receptor; CAR-T cell: chimeric antigen receptor T cell; TCF-1: transcription factor T-cell factor 1; TOX: Thymocyte selection-associated high mobility group box protein; NFAT: nuclear factor of activated T cells; NA: Naïve; CM: Central Memory; EM Effector Memory; EMRA: Terminal Effector Memory cells; FMO: Fluorescence minus one; PVR: poliovirus receptor; PVRL2: poliovirus receptor-related 2; IFN-γ: Interferon-γ; IL-2: interleukin-2; MCF: multiparametric flow cytometry; TNFα: Tumornekrosefaktor α; RT: room temperature.

The inhibitory receptor TIGIT, as well as theectonucleotidases CD39 and CD73 constitute potential exhaustion markers for T cells. Detailed analysis of these markers can shed light into dysregulation of the T-cell response in acute myeloid leukemia (AML) and will help to identify potential therapeutic targets. The phenotype and expression of transcription factors was assessed on different T-cell populations derived from peripheral blood (PB, n = 38) and bone marrow (BM, n = 43). PB and BM from patients with AML diagnosis, in remission and at relapse were compared with PB from healthy volunteers (HD) (n = 12) using multiparameter flow cytometry. An increased frequency of terminally differentiated (CD45R-CCR7-)CD8+ T cells was detected in PB and BM regardless of the disease state. Moreover, we detected an increased frequency of two distinct T-cell populations characterized by the co-expression of PD-1 or CD39 on TIGIT+CD73-CD8- T cells in newly diagnosed and relapsed AML in comparison to HDs. In contrast to the PD-1+TIGIT+CD73-CD8+ T-cell population, the frequency of CD39+TIGIT+CD73-CD8+ T cells was normalized in remission. PD-1+- and CD39+TIGIT+CD73-CD8+ T cells exhibited additional features of exhaustion by decreased expression of CD127 and TCF-1 and increased intracellular expression of the transcription factor TOX. CD8+ T cells in AML exhibit a key signature of two subpopulations, PD-1+TOX+TIGIT+CD73-CD8+- and CD39+TOX+TIGIT+CD73-CD8+ T cells that were increased at different stages of the disease. These results provide a rationale to analyze TIGIT blockade in combination with inhibition of the purinergic signaling and depletion of TOX to improve T-cell mediated cytotoxicity in AML. [ABSTRACT FROM AUTHOR]

The transcription factor TCF-1 (encoded by Tcf7) plays critical roles in several lineages of hematopoietic cells. In this study, we examined the molecular basis for Tcf7 regulation in T cells, innate lymphoid cells, and migratory conventional dendritic cells that we find express Tcf7. We identified a 1 kb regulatory element crucial for the initiation of Tcf7 expression in T cells and innate lymphoid cells, but dispensable for Tcf7 expression in Tcf7-expressing dendritic cells. Within this region, we identified a Notch binding site important for the initiation of Tcf7 expression in T cells but not in innate lymphoid cells. Our work establishes that the same regulatory element is used by distinct transcriptional controllers to initiate Tcf7 expression in T cells and ILCs.

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) 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. [ABSTRACT FROM AUTHOR]

T cell factor 1 (Tcf-1) expressing CD8+ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8+ T cells (CD8+SL) remain poorly defined. Studying CD8+ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8+SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8+ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8+SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8+SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8+SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8+SL-promoting pathway in the context of chronic viral infection. [Display omitted] • Interleukin-33 (IL-33) promotes the expansion of stem-like CD8 T cells (CD8+SL) • IL-33 signals augment chromatin accessibility of CD8+SL in chronic viral infection • IL-33 prevents the loss of Tcf-1 expression by balancing type I interferon effects • IL-33 signaling to CD8+SL preserves these cells' stemness and re-expansion capacity Stem-like Tcf-1-expressing CD8 T cells (CD8+SL) are key to immune defense in chronic infection and cancer, but the cytokine signals that promote CD8+SL cell expansion and stemness remain undefined. Marx et al. reveal that interleukin-33 assumes this role by balancing type I interferon signals and augmenting chromatin accessibility of CD8+SL. [ABSTRACT FROM AUTHOR]

In allogeneic hematopoietic stem cell transplantation, donor αβ T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1+ subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective. [Display omitted] • During early GVHD, alloreactive T cell clones enter target tissues broadly but unevenly • Late-phase GVHD is maintained within affected tissues with only minor input from blood • Tissue-resident TCF-1+ T cells maintain effector cells within most affected tissues Alloreactive T cells cause graft-versus-host disease (GVHD), but how GVHD is maintained once established is unclear. Using T cell clone tracking, parabiosis of GVHD mice and computational modeling, Sacirbegovic et al. demonstrate that progenitor-like T cells within affected tissues maintain GVHD locally, mostly independent of blood-derived T cells. [ABSTRACT FROM AUTHOR]

Lung disease is the major cause of death and hospitalization worldwide. Transcription factors such as transcription factor 7 (TCF7) are involved in the pathogenesis of lung diseases. TCF7 is important for T cell development and differentiation, embryonic development, or tumorogenesis. Multiple TCF7 isoforms can be characterized by the full-length isoform (FL-TCF7) as a transcription activator, or dominant negative isoform (dn-TCF7) as a transcription repressor. TCF7 interacts with multiple proteins or target genes and participates in several signal pathways critical for lung diseases. TCF7 is involved in pulmonary infection, allergy or asthma through promoting T cells differentiating to Th2 or memory T cells. TCF7 also works in tissue repair and remodeling after acute lung injury. The dual roles of TCF7 in lung cancers were discussed and it is associated with the cellular proliferation, invasion or metastasis. Thus, TCF7 plays critical roles in lung diseases and should be considered as a new therapeutic target. [ABSTRACT FROM AUTHOR]

CD4 T cells play a crucial role in the pathogenesis of acquired aplastic anemia (AA). Tcf-1 gene regulates T cell development and function, and it is significantly upregulated in the bone marrow CD4 T cells from patients with acquired AA. To explore the role of Tcf-1 in the pathogenesis of AA, we knocked down Tcf-1 gene in CD4 T cells of AA patients and studied the effects of Tcf-1 silencing on its downstream gene expression. Upon transfection of psiRNA into marrow CD4 T cells from bone marrow of aplastic anemia patients, the expression of Tcf-1 was significantly knocked down; consequently, expressions of c-Myc and CD44 were also significantly reduced. Our results suggest that Tcf-1 may contribute to pathogenesis of AA by regulating downstream gene expression such as c-myc and CD44. [ABSTRACT FROM AUTHOR]

The canonical Wnt signaling pathway is evolutionarily conserved and plays key roles during development of many organ systems. This pathway utilizes TCF/LEF transcription factors, β-catenin coactivator, and TLE/GRG corepressors to achieve balanced regulation of its downstream gene expression. It is well established that several Wnt ligands and their effector proteins are crucial for normal T cell development. Recent studies have also revealed critical requirements for TCF-1 in generation and persistence of functional memory CD8+ T cells, and in promoting Th2-differentiation and suppressing Th17-differentiation of activated CD4+ T cells. Activation of β-catenin facilitated CD8+ memory T cell formation, with enhanced protective capacity and extended survival of CD4+CD25+ regulatory T cells. Upregulation of Wnt ligands was observed in Drosophila in response to Toll signaling as well as in mammalian dendritic cells and macrophages upon microbial stimulation. These new findings suggest that modulating the activity of Wnt pathway may be a powerful approach to enhance protective immunity and treat autoimmune diseases. [ABSTRACT FROM AUTHOR]

CD8+ T cells responding to chronic infection adapt an altered differentiation program that provides some restraint on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8+ T cell differentiation in chronic infection has important therapeutic implications. Here, we find that the chemokine receptor CXCR3 is highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulates the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 is produced by inflammatory monocytes and fibroblasts of the splenic red pulp, where it grants stem-like cells access to signals promoting differentiation and limits their exposure to pro-survival niches in the white pulp. Consequently, functional CD8+ T cell responses are greater in Cxcl10 −/− mice and are associated with a lower viral set point. [Display omitted] • Inflammatory monocytes and fibroblasts of the splenic red pulp produce CXCL10 • CXCL10 limits exposure of stem-like CD8+ T cells to pro-survival signals • CXCL10 promotes access of virus-specific CD8+ T cells to differentiation signals • Cxcl10 −/− mice chronically infected with LCMV have a lower viral set point The chemokine CXCL10 limits formation of memory CD8+ T cells during acute infection, but its role in CD8+ T cell differentiation during chronic infection is unknown. Ozga et al. reveal that CXCL10 expression in the splenic red pulp of chronically infected mice promotes exposure of virus-specific stem-like CD8+ T cells to differentiation signals and limits access to pro-survival signals. [ABSTRACT FROM AUTHOR]

T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy. [Display omitted] • Heterogeneous PD-1 expression identifies CD8+ T cells with distinct functions in CLL • IL-10 prevents activation-induced exhaustion of CD8+ T cells and reduces CLL development • By altering chromatin in CD8+ T cells, IL-10R blockade disrupts NFAT:AP-1 cooperativity • IL-10R loss correlates with T cell exhaustion and poor survival of cancer patients T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Using a model of chronic lymphocytic leukemia, Hanna, Llaó-Cid, et al. reveal that the balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int CD8+ T cells that are associated with tumor progression or tumor control, respectively, is regulated by cell-intrinsic IL-10R signaling. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans -present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans -presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses. [Display omitted] • CXCR6 is critical for sustained tumor control mediatedby CD8+ cytotoxic T cells (CTLs) • CXCR6 optimizes CTL interactions with the CCR7+ DC3 state of conventional DCs • DC3s trans -present IL-15 to TCF-1neg effector-like CTLs to sustain their survival in the TME • DC3s densely cluster in T cell-rich perivascular niches of the tumor stroma Intravital imaging reveals how the chemokine receptor CXCR6 positions CD8+ cytotoxic T cells in a distinct perivascular niche of the tumor stroma that is populated by CCR7+ dendritic cells expressing the CXCR6-ligand CXCL16 and trans -presenting the cytokine IL-15. This molecular checkpoint allows for the survival and expansion of CD8+ T cells to enable a potent anti-tumor immune response. [ABSTRACT FROM AUTHOR]