Expression Of T Cell Factor 1 Research Articles

TCF1 dosage determines cell fate during T cell development.

Loss-of-function studies have shown that transcription factor T cell factor-1 (TCF1), encoded by the Tcf7 gene, is essential for T cell development in the thymus. We discovered that the Tcf7 expression level is regulated by E box DNA binding proteins, independent of Notch, and regulates αβ and γδ T cell development. Systematic interrogation of the five E protein binding elements (EPE1-5) in the Tcf7 enhancer region showed lineage-specific utilization. Specifically, loss-of-function analysis revealed that only EPE3 plays a critical role in supporting αβ T cell development, while EPE1, 3, and 5 regulate the γδ T cell maturation and functional cell fate decision. The importance of EPE3 in supporting both lineages may stem from its unique capacity to interact with the Tcf7 transcriptional start site. Together, these studies demonstrate that the precise dosage of TCF1 expression mediated by distinct EPEs generates a balanced output of T cells from the thymus.

Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state

T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor Tcell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature Tcells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.

T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer

The presence of precursor to exhausted (Tpex) CD8+ Tcells is important to maintain robust immunity following treatment with immune checkpoint inhibition (ICI). Impressive responses to ICI are emerging in patients with stage II-III mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC). We found 64% of dMMR and 15% of mismatch repair-proficient (pMMR) stage III CRCs had a high frequency of tumor infiltrating lymphocytes (TIL-hi). Furthermore, expression of TCF-1 (Tcf7) by CD8+ Tcells predicted improved patient prognosis and Tpex cells (CD3+CD8+TCF-1+PD-1+) were abundant within lymphoid aggregatesof stage III CRCs. In contrast, CD3+CD8+TCF-1-PD-1+ cells were more abundant at the invasive front and tumor core, while γδ Tcells were equally abundant in all tumor areas. Interestingly, no differencesin the frequency of Tpex cells were observed between TIL-hi dMMR and TIL-hi pMMR CRCs. Therefore, Tpex cell function and ICI response rates in TIL-hi CRC warrants further investigation.

Clinicopathological implications of immunohistochemical expression of TBX21, CXCR3, GATA3, CCR4, and TCF1 in nodal follicular helper T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.

The classification of nodal peripheral T-cell lymphoma (PTCL) has evolved according to histology, cell-of-origin, and genetic alterations. However, the comprehensive expression pattern of follicular helper T-cell (Tfh) markers, T-cell factor-1 (TCF1), and Th1- and Th2-like molecules in nodal PTCL is unclear. Eighty-two cases of nodal PTCL were classified into 53 angioimmunoblastic T-cell lymphomas (AITLs)/nodal T-follicular helper cell lymphoma (nTFHL)-AI, 18 PTCLs-Tfh/nTFHL-not otherwise specified (NOS), and 11 PTCLs-NOS according to the revised 4th/5th World Health Organization classifications. Immunohistochemistry for TCF1, TBX21, CXCR3, GATA3, and CCR4 was performed. TCF1 was highly expressed in up to 68% of patients with nTFHL but also in 44% of patients with PTCL-NOS (p > .05). CXCR3 expression was higher in AITLs than in non-AITLs (p = .035), whereas GATA3 expression was higher in non-AITL than in AITL (p = .007) and in PTCL-Tfh compared to AITL (p = .010). Of the cases, 70% of AITL, 44% of PTCLTfh/ nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the TBX21 subtype; and 15% of AITL, 38% of PTCL-Tfh/nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the GATA3 subtype. The others were an unclassified subtype. CCR4 expression was associated with poor progression-free survival (PFS) in patients with PTCL-Tfh (p < .001) and nTFHL (p = .023). The GATA3 subtype showed poor overall survival in PTCL-NOS compared to TBX21 (p = .046) and tended to be associated with poor PFS in patients with non-AITL (p = .054). The TBX21 subtype was more prevalent than the GATA3 subtype in AITL. The GATA3 subtype was associated with poor prognosis in patients with non-AITL and PTCL-NOS.

Characterization of TCF-1 and its relationship between CD8+ TIL densities and immune checkpoints and their joint influences on prognoses of lung adenocarcinoma patients.

T cell factor-1 (TCF-1) + stem-like tumor-infiltrating lymphocytes (stem-like TILs) are important memory cells in the tumor microenvironment. However, their relationship with clinicopathological features, CD8+ TIL densities, immune checkpoint inhibitors (ICs), and prognostic values remain unknown for lung adenocarcinomas (LUADs). In this study, we aimed to characterize TCF-1+ TILs and their prognostic significance in patients with surgically resected LUADs. Expression of TCF-1, CD8, and ICs including programmed death-1 (PD-1), lymphocyte activating-3 (LAG-3), and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) in TILs were estimated using immunohistochemistry of resected LUADs. The association between TCF-1 expressions and clinicopathological characteristics of patient prognoses were analyzed. Positive TCF-1 expression significantly correlated with advanced pathological stage, tumor grade, CD8+ TILs density, TIM-3 expression, LAG-3 expression, and PD-1 expression. TCF-1 positivity was significantly associated with a better recurrence-free survival (RFS), and overall survival (OS). Subgroup analysis revealed that the TCF-1+/CD8+ group had the best RFS and OS, while the TCF-1-/CD8- group had the worst RFS and OS. Similarly, patients with TCF-1 + PD-1- had the best prognoses and patients with TCF-1-PD-1+ had the worst prognoses. TCF-1 had relatively high positive expression and special clinicopathological features in patients with LUAD. TCF-1+ TILs were related to CD8 density, TIM-3 expression, LAG-3 expression, and PD-1 expression, and were associated with better prognoses in LUAD patients. A combination of TCF-1 and CD8 densities or PD-1 expression further stratified patients into different groups with distinct prognoses.

Abstract P3-08-07: Self-renewal signatures of peripheral blood T cells are associated with successful engraftment to establish a humanized mouse model of breast cancer

Abstract Background: Stable humanized immune mice transplanted with peripheral blood mononuclear cells (PBMCs) derived from breast cancer patients are important models for assessing the tumor immune responses and the tumor immune microenvironment in breast cancer, helping to advance both pre-clinical and clinical research. The PBMCs of breast cancer patients exhibit various differences from those of healthy individuals depending on the stage of cancer progression, subtype, and type of treatment. Recent studies indicate an association of the self-renewal signatures of T cells with successful generation of a humanized mouse model; however, the optimal T cell signature for the successful generation of a humanized mouse model derived from cancer patient cells is poorly understood. Therefore, we examined the relationship between the signature of T cell subsets, focusing on the self-renewal signatures, in PBMCs derived from patients with breast cancer and the successful generation of a humanized immune mouse model. Materials and Methods: We collected PBMCs from 12 patients with breast cancer. All samples were stimulated with interleukin-2 and beads coated with CD3 and CD28 agonist antibodies to expand T cells. After washing, 1 × 10^7 cells/mouse were intraperitoneally injected into NOD/Shi-scid IL2rgamma (null) (NOG) mice. Transplants were performed on three mice per case. Successful engraftment of immune cells into NOG mice was defined by the presence of human CD45+ cells in one or more mice. Self-renewal signatures of in vitro expanded T cells before injection into NOG mice, including the markers T cell factor-1 (TCF-1), CD45RA, CCR7, CD95, and CXCR3, were determined using flow cytometry, mass cytometry and quantitative RT-PCR. Comparisons between groups of data were evaluated by t-test. Results: The success rate of engraftment of immune cells derived from breast cancer patients into NOG mice was 66.7% (8 out of 12 patients). After expansion, the magnitude of the CD8+ stem cell memory subset and the TCF-1 expression level on the CD4+ and CD8+ T cells in the engrafted group were significantly higher than those in non-engrafted group. TCF-1 and CCR7 mRNA levels in the engrafted group were upregulated compared with those in non-engrafted group. The success of engraftment was not associated with clinical characteristics such as breast cancer progression, subtype, or prior chemotherapy treatment. Conclusion: The self-renewal signatures of T cells from breast cancer patients were associated with successful engraftment of a humanized mouse model. These results suggest that prior identification of the self-renewal signatures of the T-cell population is of direct relevance to the appropriate design of a pre-clinical model for testing immunotherapies and for elucidating the characteristics of the tumor immune microenvironment. Citation Format: Yukiko Fukui, Kosuke Kawaguchi, Ryuji Murakami, Wei Li, Yuki Nakamura, Yurina Maeshima, Sunao Tanaka, Shinpei Kawaoka, Eiji Suzuki, Masakazu Toi. Self-renewal signatures of peripheral blood T cells are associated with successful engraftment to establish a humanized mouse model of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-07.

Liver X receptor controls follicular helper T cell differentiation via repression of TCF-1

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 invivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXRβ-deficient 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+ Tcells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ Tcells. 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.

Self-Renewing CD8+ T-cell Abundance in Blood Associates with Response to Immunotherapy.

Treatment with immune checkpoint blockade (ICB) often fails to elicit durable antitumor immunity. Recent studies suggest that ICB does not restore potency to terminally dysfunctional T cells, but instead drives proliferation and differentiation of self-renewing progenitor T cells into fresh, effector-like T cells. Antitumor immunity catalyzed by ICB is characterized by mobilization of antitumor T cells in systemic circulation and tumor. To address whether abundance of self-renewing T cells in blood is associated with immunotherapy response, we used flow cytometry of peripheral blood from a cohort of patients with metastatic non-small cell lung cancer (NSCLC) treated with ICB. At baseline, expression of T-cell factor 1 (TCF1), a marker of self-renewing T cells, was detected at higher frequency in effector-memory (CCR7-) CD8+ T cells from patients who experienced durable clinical benefit compared to those with primary resistance to ICB. On-treatment blood samples from patients benefiting from ICB also exhibited a greater frequency of TCF1+CCR7-CD8+ T cells and higher proportions of TCF1 expression in treatment-expanded PD-1+CCR7-CD8+ T cells. The observed correlation of TCF1 frequency in CCR7-CD8+ T cells and response to ICB suggests that broader examination of self-renewing T-cell abundance in blood will determine its potential as a noninvasive, predictive biomarker of response and resistance to immunotherapy.

METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis.

Alteration of N6-methyladenosine (m6A) is closely linked to spanning biological processes including osteoporosis (OP) development. This research focuses on the function of methyltransferase like 14 (METTL14) in bone turnover and its interaction with T cell factor 1 (TCF1). A mouse model of OP was established by ovariectomy (OVX). The bone mass parameters were evaluated by micro-CT analysis. Mouse MC3T3-E1 cells and mouse bone marrow macrophages (BMMs) were induced for osteogenic or osteoclastic differentiation, respectively, for in vitro experiments. The osteogenesis or osteoclasis activity was analyzed by measuring the biomarkers such as OPG, ALP, NFATC1, CTSK, RANKL, and TRAP. RT-qPCR and IHC assays identified reduced METTL14 expression in bone tissues of osteoporotic patients and ovariectomized mice. Artificial METTL14 overexpression increased bone mass of mice and promoted osteogenesis whereas suppressed osteoclasis both in vivo and in vitro. METTL14 promoted TCF1 expression through m6A mRNA methylation, and TCF1 increased the osteogenic activity by elevating the protein level of RUNX2, a key molecule linked to bone formation. In rescue experiments, TCF1 restored the RUNX2 level and osteogenic activity of cells suppressed by METTL14 silencing. In summary, this research demonstrates that METTL14 plays a protective role against OP by promoting the TCF1/RUNX2 axis.

Abstract 1240: Peripherally measured T cell self-renewal capacity associates with response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC)

Abstract Recent studies have suggested that ICB does not primarily restore function to terminally exhausted T cells, but instead drives proliferation and differentiation of progenitor T cells into fresh effector cells. T cell factor 1 (TCF1) marks and maintains T cell self-renewal while repressing differentiation and has been associated with increased antitumor activity. These findings suggest ICB may depend on the continued availability of self-renewing TCF1+ progenitor T cells as the source of fresh effector cells. We hypothesized that characterizing the immunophenotype of T cells in the peripheral blood, with a focus on markers of self-renewal, might be predictive of ICB response. Utilizing an institution-wide biospecimen repository, we evaluated peripheral blood samples using multi-parametric flow cytometry from patients with metastatic NSCLC treated with single-agent ICB who experienced durable clinical benefit (DCB; &amp;gt;1 year of treatment and/or clinical response &amp;gt;1 year) or primary resistance (RES; &amp;lt;6 months of treatment with evidence of disease progression). Our analysis focused on a CCR7- T cell subset, which is characterized by lower proportions of TCF1+ cells but increase during active immune responses. We analyzed samples collected from a cohort of 22 patients, 11 of whom had DCB and 11 with RES. In the pre-treatment samples (n=22), we determined that the frequency of TCF1+CCR7- CD8+ T cells was significantly higher in patients with DCB compared to patients with RES (32.6% v. 19.0%; P = 0.0452). Importantly, the median progression free survival was 17.0 months in patients with TCF1+ frequency above the median compared to 3.0 months in patients with TCF1+ frequency below the median (HR 0.43; P = 0.0185). Among the on-treatment samples (n=19), there was an increased frequency of PD1+ expression within the CCR7- CD8+ T cell subset compared to the paired baseline samples. Examination of those therapy-expanded PD1+ T cells revealed differences in the composition of TCF1+ versus TCF1- fractions in relation to treatment outcome. The mean ratio of TCF1+ to TCF1- amongst PD1+CCR7- T cells on-treatment was found to be significantly higher in the DCB group (1.483 [DCB] v. 0.4791 [RES], P=&amp;lt;0.0001). In this analysis, we identified a pattern of pre-and on-treatment T cell populations that correlates with durable benefit from ICB in patients with NSCLC. We observed that the frequency of TCF1 expression in the more differentiated effector memory T cell subsets prior to treatment correlates with DCB. While on treatment, both groups experienced expansion of PD1+ CD8 T cells, but the presence of greater fractions of TCF1+ T cells in the PD1+ CD8 T cell population correlates with DCB. This finding suggests that persistence and mobilization of self-renewing progenitor T cells is associated with long-lived ICB-induced anti-tumor activity. Citation Format: Rohan Maniar, Peter H. Wang, Robert S. Washburn, Naiyer A. Rizvi, Steven L. Reiner, Brian S. Henick. Peripherally measured T cell self-renewal capacity associates with response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1240.

Changes in the expression of T-cell factor-1 in follicular helper T cells reflect the condition of systemic lupus erythematosus patients

ObjectiveThis study aimed to identify changes in T-cell factor-1 (TCF1) in circulating T-cell subsets of systemic lupus erythematosus (SLE) patients and to explore their significance in SLE. MethodsPeripheral blood was collected from 41 SLE patients and 45 healthy controls (HCs). TCF1 in follicular helper T (TFH), follicular regulatory T (TFR) and regulatory T (Treg) cells was analyzed by flow cytometry. Interleukin-21 (IL-21), programmed death receptor 1 (PD-1) and killer cell lectin-like receptor G1 (KLRG1) were detected and compared among TFH subsets sorted according to TCF1 and CD62L expression. Correlation analyses were conducted between TCF1-related TFH cell subsets and autoantibody levels, systemic lupus erythematosus disease activity index (SLEDAI), and plasmablast levels of SLE patients. ResultsAbsolute numbers of TCF1- TFH and TCF1+ Treg cells were increased in SLE patients. According to TCF1 and CD62L expression, circulating TFH cells and Tregs were sorted into four subsets. CD62L+TCF1+ TFH cell percentages were decreased, and CD62L-TCF1- TFH cells were increased. CD62L+TCF1+ Treg cell percentages were increased, and CD62L-TCF1- Treg cell percentages were decreased. KLRG1+ percentages in CD62L-TCF1-TFH were higher in SLE patients than in HCs. Functionally, CD62L+TCF1+ TFH cells had stronger IL-21 secretion, while CD62L-TCF1-TFH cells had weaker IL-21 secretion and lower PD-1 expression. TCF1- and CD62L-TCF1- TFH numbers were positively correlated with anti-ribosomal P, anti-dsDNA and SLEDAI. ConclusionThe increased TFH cells in SLE patients were mostly TCF1-negative subsets with weakened function. Changes in TCF1-related subsets can reflect the condition and abnormal humoral immunity of SLE patients.

The transcription factor T cell factor 1 (TCF1) expression is elevated in vaccine-elicited CD8+ T cells and negatively regulated by T-bet

Abstract T cells that express high levels of TCF1 display stem cell-like properties and give rise to effector-like cells that protect during chronic infections and cancer. Due to their increased responsiveness to checkpoint blockade, TCF1hi T cells are now recognized as promising targets for immunotherapies. We found that adjuvanted subunit vaccine-elicited T cells (Tvac) express significantly higher levels of TCF1 than T cells responding to infections (Tinf). In exploring the underlying causes for such high expression of TCF1 in Tvac, we examined the role of sustained TCR and inflammatory mediators in Tvac TCF1 regulation. Using Nr4a3-Tocky reporter mice and pMHCI antibody blockade, we found that TCR mediated signals regulate Tvac TCF1 to a limited degree. In line with previous reports, TCF1 expression in Tvac inversely correlated with adjuvant-elicited pro-inflammatory signals, increasing concomitantly with the rapid decline of cytokines after adjuvant administration. Further, the addition of TLR9 ligand CpG increased inflammatory cytokine production as it reduced TCF1 expression. However, in contrast to previous work, anti-IL-12 or anti-IFNγ treatment failed to reverse the lower TCF1 expression induced by CpG. More surprisingly, we found that Tvac TCF1 is regulated independently of Foxo1 even while Foxo1 plays its canonical role in facilitating TCF1 expression under inflammatory conditions. Inflammation does however negatively regulate TCF1 in a T-bet dependent manner, such that T-bet KO Tvac maintained high TCF1 expression even when inflammation was increased. Our data highlight differences in the transcriptional regulation of vaccine- and infection-elicited T cells and provide insights into the mechanism of TCF1 regulation.

Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR–T-cell responses against ALL

AbstractChimeric antigen receptor (CAR)–T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR–T-cell expansion and memory-like cell formation. This leads to improved CAR-T–mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1–deficient CAR-T cells into TCF-1+ precursor exhausted T cells (TPEX) characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 messenger RNA (mRNA); its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR–T-cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1− CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR–T-cell population. Our findings demonstrate the pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR–T-cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR–T-cell longevity and potency that may be manipulated for improved therapeutic efficacy.

Increased Frequency of TOX+ CD39+ TIGIT+ CD73- CD8+ T Cells in Patients with Newly Diagnosed AML

Increased Frequency of TOX+ CD39+ TIGIT+ CD73- CD8+ T Cells in Patients with Newly Diagnosed AML

The Transcription Factor TCF1 in T Cell Differentiation and Aging.

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.

The regulation of transcription factor T cell factor 1 (TCF1) in vaccine-elicited CD8+ T cells

Abstract Our lab has developed a subunit vaccination regimen that induces a highly robust T cell response. These vaccine-elicited CD8+ T cells (Tvac) are phenotypically, functionally and metabolically distinct from infection-elicited CD8+ T cells (Tinf). In contrast to Tinf, almost all Tvac rapidly acquire a memory phenotype (CD127hi, KLRG1lo). This suggests that Tvac could be differentially transcriptionally programmed to commit to a memory, rather than effector, cell fate. The transcription factor TCF1 (encoded by tcf7) is essential for CD8+ T cell memory in response to infection. Since high TCF1 expression is also important for the generation of stem-like T cells with long-term survival capacity and anti-tumor properties, it is now recognized as a promising target for immunotherapies. However, little is known about how TCF1 is regulated in response to subunit vaccination. We find that, in striking contrast to Tinf, TCF1 expression is actually increased in Tvac after vaccination. As others have shown, we also find that increasing inflammation during vaccination by the addition of TLR9 agonist CpG reduces TCF1 expression in Tvac, skewing their memory phenotype towards the effector phenotype (CD127lo, KLRG1hi) and compromising their long-term memory. While the loss of TCF1 in this context has conventionally been ascribed to inflammatory receptors, utilizing reporter Nur77GFP mice, we also observe an altered duration and frequency of TCR triggering in the context of inflammation. Our data indicates a complex, previously unappreciated interplay between inflammatory and TCR-mediated signals in the regulation of TCF1.

Attenuation of Wnt/β-catenin signaling in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

DeTOXifying exhausted T cells

DeTOXifying exhausted T cells

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients.

The Wnt pathway is involved in the progression of breast cancer (BC). We aimed to evaluate the expression of some components of the Wnt pathway (β-catenin, FZD4 (frizzled receptor 4), LRP5 (low-density lipoprotein receptor-related protein 5), LRP6, and TCF1 (T-cell factor 1)) to detect potential associations with NHERF1 (Na+/H+ exchanger regulatory factor 1) protein. Besides, we assessed their impact on patients’ clinical outcome. We evaluated 220 primary BC samples by immunohistochemistry (IHC) and protein localization by immunofluorescence. We found a significant correlation between NHERF1 and FZD4, LRP5, LRP6, and TCF1. Univariate analysis showed that the overexpression of β-catenin (p < 0.0001), FZD4 (p = 0.0001), LRP5, LRP6, and TCF1 (p < 0.0001 respectively) was related to poor disease-free survival (DFS). A Kaplan-Meier analysis confirmed univariate data and showed a poor DFS for cNHERF1+/FZD4+ (p = 0.0007), cNHERF1+/LRP5+ (p = 0.0002), cNHERF1+/LRP6+ (p < 0.0001), and cNHERF1+/TCF1+ phenotypes (p = 0.0034). In multivariate analysis, the expression of TCF1 and β-catenin was an independent prognostic variable of worse DFS (p = 0.009 and p = 0.027, respectively). In conclusion, we found that the overexpression of β-catenin, FZD4, LRP5, LRP6, and TCF1 was associated with poor prognosis. Furthermore, we first identified TCF1 as an independent prognostic factor of poor outcome, indicating it as a new potential biomarker for the management of BC patients. Also, the expression of Wnt pathway proteins, both alone and in association with NHERF1, suggests original associations of biological significance for new studies.

TCF1 expression marks self-renewing human CD8+ T cells

AbstractExpression of the transcription factor T-cell factor 1 (TCF1) identifies antigen-experienced murine CD8+ T cells that retain potential for lymphoid recirculation and the ability to self-renew while producing more differentiated effector cells. We found that CD8+ T cells in the blood of both healthy and chronically infected humans expressed TCF1 at 3 distinct levels: high (TCF1-hi), intermediate (TCF1-int), and low (TCF1-lo). TCF1-hi cells could be found within both the naive and memory compartments and were characterized by relative quiescence and lack of immediate effector function. A substantial fraction of TCF1-int cells were found among memory cells, and TCF1-int cells exhibited robust immediate effector functions. TCF1-lo cells were most enriched in effector memory cells that expressed the senescence marker CD57. Following reactivation, TCF1-hi cells gave rise to TCF1-lo descendants while self-renewing the TCF1-hi progenitor. By contrast, reactivation of TCF1-lo cells produced more TCF1-lo cells without evidence of de-differentiating into TCF1-hi cells. Flow cytometric analyses of TCF1 expression from patient specimens may become a useful biomarker for adaptive immune function in response to vaccination, infection, autoimmunity, and cancer.