EBV-Specific CD8+ T-Cells Are Not Functionally Impaired in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1723-1723
Author(s):  
Tom Hofland ◽  
Iris de Weerdt ◽  
Sanne Terpstra ◽  
Ester B.M. Remmerswaal ◽  
Ineke J.M. ten Berge ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Synapse Formation ◽  
T Cell Differentiation ◽  
Lymphocytic Leukemia ◽  
Immune Synapse ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Chronic lymphocytic leukemia (CLL) is characterized by a tumor induced T-cell dysfunction, which leads to increased susceptibility to infections and a decreased immunosurveillance (Görgün et al. JCI, 2005). Furthermore, T-cell dysfunction impairs novel treatment strategies that rely on T-cell mediated effects. The dysfunction of T-cells in CLL is characterized by an inability to form immune synapses, increased expression of exhaustion markers and impaired cytotoxicity and proliferative capacity (Ramsay et al. JCI 2008; Ramsay et al. Blood 2012; Riches et al. Blood 2013). However, we recently found that CMV-specific CD8+ T-cells from CLL patients are functionally intact with respect to cytokine production, cytotoxicity and immune synapse formation when compared to age-matched healthy controls (HC)(te Raa et al. Blood 2014). The finding that specific subsets of T-cells in CLL patients are functionally intact challenges the concept of a global T-cell dysfunction in CLL. Whether intact functionality of CMV-specific T-cells is a rare exception or whether T-cell functionality is indeed more heterogeneous is currently unknown. Aim To analyze T-cell function heterogeneity in CLL, we studied the immunophenotype and functionality of CD8+ T-cells specific for Epstein-Barr-virus (EBV), another widely common chronic latent viral infection. Methods EBV-specific CD8+ T-cells were analyzed using EBV tetramers and 14-color flow cytometry in 42 untreated CLL patients and 23 age-matched HC. We studied T-cell differentiation based on surface markers CD45RA, CCR7, CD27 and CD28 and 2 master regulators of T-cell differentiation, the transcription factors T-bet and Eomes. We also measured expression of exhaustion markers (PD-1, CD244 and CD160), functional markers (such as KLRG1, CD127, granzyme B, granzyme K and Ki-67) and homing markers (CXCR3 and CX3CR1). To study the functionality of EBV-specific CD8+ T-cells, we determined cytokine production and polyfunctionality after stimulation with EBV-derived peptides. Results Using a comprehensive T-cell differentiation staining we found that when compared to HC, EBV-specific T-cells in CLL patients are further differentiated with a significantly smaller percentage of "early" effector memory cells (also called EM1, CD45RA- CCR7- CD27+ CD28+; CLL=39.6% vs HC=57.68%). These results are mirrored by the expression patterns of the transcription factors T-bet and Eomes; 25.79% EBV-specific T-cells of CLL patients display a T-bethigh Eomeshigh phenotype vs 17.44% in HC. In comparison with HC, EBV-specific T-cells in CLL patients show higher expression of exhaustion markers CD244 and CD160 (MFI 4896.42 vs 3130.56 and 2320.09 vs 1097.38, respectively), but not PD-1. However, there were no significant differences in granzyme B and K expression in EBV-specific T-cells, suggesting an unaltered cytotoxic potential. On a functional level, no differences between CLL and HC were found with respect to production of the cytokines TNFα, IFNγ, IL-2 and MIP-1β of EBV-specific T-cells after peptide stimulation. Also, degranulation (measured as CD107a+ cells) was similar between CLL patients and healthy controls after peptide stimulation. Finally, polyfunctionality of EBV-specific T-cells of CLL patients was comparable with HC. We are currently determining cytotoxicity and immune synapse formation. Conclusion So far, although the phenotype may suggest an increased exhaustive state, we have not observed signs of dysfunction of EBV-specific T-cells in CLL patients when compared to HC. We are currently performing experiments to test cytotoxicity and ability to produce immune synapses of EBV-specific T-cells (which we will be able to present during the ASH meeting). Based on these results, we will be able to conclude if EBV-specific CD8+ T-cells are also functionally intact in CLL patients, and whether this population joins CMV-specific T-cells as a subset that eludes CLL induced T-cell dysfunction. T-cell dysfunction in CLL needs to be better understood in order to improve anti-tumor immunotherapies that rely on T-cell mediated effects. T-cell populations that escape suppression may be good targets for future therapies to build around. Disclosures No relevant conflicts of interest to declare.

scholarly journals Differential Immune Responses in Epidemic and Endemic Tanzanian Kaposi Sarcoma Patients

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 202s-202s
Author(s):  
J.D. Mwaiselage ◽  
S. Lidenge ◽  
J.R. Ngowi ◽  
G. Haynatzki ◽  
C. Wood ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Immune Responses ◽  
Kaposi Sarcoma ◽  
Neutralizing Antibody ◽  
T Cell Differentiation ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Hiv 1

Background: Mechanisms underlying Kaposi sarcoma (KS) development are unclear. The high incidence of KS in HIV-1+ individuals implicates immune dysregulation in epidemic KS (EpKS) development. In African endemic KS (EnKS), the immune response is uncharacterized. Aim: The aim was to assess a comparative quantification between newly diagnosed Tanzanian EpKS and EnKS patients, and asymptomatic controls. We also report the first comparison of KSHV NAb prevalence and titer between EpKS and EnKS patients. Methods: To compare innate and adaptive immune responses, we recruited histologically confirmed Tanzanian EpKS and EnKS patients, as well as noncancer controls. After differential detection of KSHV nucleic acids in tissues, neutralizing antibody (NAb), levels of cytokines/chemokines, and T-cell differentiation subsets were quantified. The Mann-Whitney U-test was used to assess median differences between groups. All tests were 2-tailed and P-values < 0.05 were considered significant. Results: A total of 180 patients have been recruited in this study. In addition, a comparable 25 EpKS and 10 EnKS as well as 10 noncancer controls were recruited for this study. KSHV was significantly more frequently detected in EpKS patients than in EnKS. While all EpKS, and some EnKS patients mounted NAb responses, the EpKS patients had higher prevalence and titer of NAb compared with EnKS patients ( P = 0.001). Levels of the cytokines IP-10 and IL-10 were higher in EpKS vs EnKS patients ( P = 0.006 and P = 0.005 respectively), whereas, IL-4 was lower in EpKS vs EnKS patients ( P = 0.004). The levels of all 14 cytokines/chemokines measured were comparable between EnKS patients and HIV− controls ( P < .05 ). The distribution of CD4+ and CD8+ T-cells was similar between EpKS and EnKS such as naive and effector T-cells were depleted while central memory T-cells were elevated in both KS forms. Conclusion: The detection of similar abnormalities in T-cell differentiation subsets in both EpKS and EnKS as compared with controls, suggests that KSHV-induced T-cell dysfunction plays a major role in the disease, and that HIV-1 coinfection is only exacerbating and accelerating KSHV pathogenesis and KS development.

Abstract 60: Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment

2021 ◽  
Author(s):  
Charly R. Good ◽  
Shunichiro Kuramitsu ◽  
Parisa Samareh ◽  
Greg Donahue ◽  
Kenichi Ishiyama ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Differentiation ◽  
Cell Dysfunction ◽  
Car T Cell ◽  
Car T ◽  
T Cell Dysfunction

scholarly journals 663 Media based on the metabolic composition of tumor interstitial fluid reveals persistent T cell dysfunction induced through arginine deprivation and exposure to the oncometabolite phosphoethanolamine

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A691-A691
Author(s):  
Yupeng Wang ◽  
Chufan Cai ◽  
Dayana Rivadeneira ◽  
Alexander Muir ◽  
Greg Delgoffe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Interstitial Fluid ◽  
Cytokine Production ◽  
Cell Dysfunction ◽  
Kennedy Pathway ◽  
T Cell Dysfunction ◽  
Tumor Interstitial Fluid

BackgroundWhile CD8 T cells are crucial for anti-tumor immunity, tumor infiltrating CD8 T cells encounter stressors which deviate their differentiation to a dysfunctional, exhausted phenotype. T cell functions are closely regulated by T cell metabolism, and the dysfunctional vasculature in tumor tissues and the deregulated metabolism of tumor cells lead to depletion of nutrients and accumulation of metabolic wastes in the tumor microenvironment (TME). Thus, the unbalanced levels of the nutrients and the metabolic wastes might skew the metabolism of T cells thus contributing to T cell dysfunction.MethodsOvalbumin-specific OT-I cells were activated with SIINFEKL/IL2 and cultured with IL2. The tumor interstitial fluid media (TIFM) was formulated based on the concentrations of the metabolites measured in the tumor interstitial fluid of pancreatic ductal adenocarcinoma.1 Purified arginine and phosphoethanolamine (PEtn) were used to change their levels in TIFM/RPMI1640 culture. Expression level of cytokines and PD-1 was measured by flow cytometry.ResultsWe sought to determine how T cells would differentiate, in vitro, if they were exposed only to the metabolites present in the TME. Using media formulated to model the metabolic composition of tumor interstitial fluid (TIFM),1 we show that CD8 T cells develop features of exhausted T cells in the TIFM culture: reduced proliferation, increased expression of PD-1 and decreased cytokine production. Using 'dropout' and 'add-back' approaches, we found arginine levels as a major contributor to the proliferation defect observed in TIFM-cultured T cells. Arginine was sufficient to restore proliferative capacity to T cells cultured in TIFM, but had no effect on the inhibited cytokine production. We then asked which metabolites were enriched in the TIFM, finding that PEtn, an intermediate in the ethanolamine branch of the Kennedy pathway and an oncometabolite enriched in the interstitial of many solid tumors, up-regulates PD-1 expression and compromises the cytokine production of the cells in culture. Depletion of Pcyt2, the metabolizing enzyme of PEtn and the rate limiting enzyme in the Kennedy pathway, makes CD8 T cells resistant to the effects of PEtn.ConclusionsOur data shows that the metabolic environment in the TME can be recapitulated in vitro and is sufficient to drive T cell dysfunction. Arginine depletion acts as a major inhibitor of T cell proliferation in the TME, but the oncometabolite PEtn drives a hypofunctional effector fate of T cells. Targeting PEtn metabolism via Pcyt2 depletion or inhibition is a potential target to reinvigorate T cells and enhance anti-tumor immunity.ReferenceSullivan MR, Danai LV, Lewis CA, Chan SH, Gui DY, Kunchok T, Dennstedt EA, Vander Heiden MG, Muir A. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife 2019;;8:e44235. doi: 10.7554/eLife.44235. PMID: 30990168; PMCID: PMC6510537.

scholarly journals 668 Lipid-instructed metabolic rewiring unleash the anti-tumor potential of CD8+ T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A696-A696
Author(s):  
Teresa Manzo ◽  
Carina Nava Lauveson ◽  
Teresa Maria Frasconi ◽  
Silvia Tiberti ◽  
Ignazio Caruana ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mitochondrial Function ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Metabolic Reprogramming ◽  
Tumor Control ◽  
Metabolic Fitness

BackgroundAdoptive cell therapy (ACT) harnesses the immune system to recognise tumor cells and carry out an anti-tumor function. However, metabolic constraints imposed by the tumour microenvironment (TME) suppress anti-tumor responses of CTL by reshaping their metabolism and epigenetic landscape. We have recently demonstrated that progressive accumulation of specific long-chain fatty acids (LCFAs) impair mitochondrial function and drives CD8+ T cell dysfunction. In this scenario, maintaining T cells in a less-differentiated state and with high metabolic plasticity during ex vivo T cell production and after infusion may have a strong therapeutic impact. Here, we propose a novel strategy to boost ACT efficacy by implementing T cell long-term functionality, metabolic fitness and preventing exhaustion through lipid-induced mitochondrial rewiring.MethodsWe screen different LCFAs and assess their ability to shape CD8+ T cell differentiation using multi-parametric flow cytometry, proliferation and cytotoxic assays, together with a complete transcriptomic and epigenomic profiling. Metabolic reprogramming of lipid-treated CD8+ T cell was examined by bioenergetic flux measurements paired with metabolomic and lipidomic analysis. Finally, the anti-tumor responses of lipid-instructed CD8 T cells was evaluated in a melanoma mouse model, known to poorly respond to immunotherapy.ResultsLCFAs-treated CD8+ T cells are endowed with highly effector and cytotoxic features but still retaining a memory-like phenotype with decreased PD1 protein levels. Consistently, analysis of the bioenergetic profile and mitochondrial activity has shown that LCFA-instructed CD8+ T cells display a greater mitochondrial fitness. Thus, in vitro LCFA-instructed CD8+ T cells are characterized by higher mitochondrial fitness, potent functionality, memory-like phenotype and PD-1 down-regulation, overall evoking the ideal T cell population associated with a productive anti-tumor response. The therapeutic potential of CD8 T cells lipid-induced metabolic rewiring was further confirmed in vivo. ACT performed with LCFA-reprogrammed CD8 T cells induces higher frequency of memory T cells, which show high polyfunctionality and mitochondrial function, decreased PD1 expression, ultimately resulting in improved tumor control. In addition, LCFA-induced metabolic rewiring during manufacturing of human CAR-redirected T cells, generated a CD8+ T cell memory-like population with higher mitochondrial fitness coupled with a much potent cytotoxic activity.ConclusionsThese results suggest that LCFAs dictate the fate of CD8+ T cell differentiation and could be considered as a molecular switch to fine-tune memory T cell formation and metabolic fitness maintenance, linking lipid metabolism to anti-tumor surveillance. This will be of fundamental importance for a new generation of adoptive T cell-based therapies.Ethics ApprovalThe experiments described were performed in accordance with the European Union Guideline on Animal Experiments and mouse protocols were approved by Italian Ministry of Health and the IEO Committee.

scholarly journals TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

2017 ◽  
Vol 199 (12) ◽  
pp. 4091-4102 ◽  
Author(s):  
Nina Chi Sabins ◽  
Olesya Chornoguz ◽  
Karen Leander ◽  
Fred Kaplan ◽  
Richard Carter ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Differentiation ◽  
Effector Memory ◽  
Memory T Cell

scholarly journals Role of PD-1 during effector CD8 T cell differentiation

2018 ◽  
Vol 115 (18) ◽  
pp. 4749-4754 ◽  
Author(s):  
Eunseon Ahn ◽  
Koichi Araki ◽  
Masao Hashimoto ◽  
Weiyan Li ◽  
James L. Riley ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Lcmv Infection

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti–PD-L1 or anti–PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

Functional Screening Studies Identify Combinational Activity of PD-L1 and CD200 In Mediating Dysfunctional T Cell Immunological Synapse Formation In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 696-696
Author(s):  
Alan G. Ramsay ◽  
Andrew James Clear ◽  
Alexander Davenport ◽  
Rewas Fatah ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Suppression ◽  
Neutralizing Antibodies ◽  
Synapse Formation ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Immune Synapse ◽  
Cell Synapse

Abstract Abstract 696 The ability of cancer cells to modulate the immune microenvironment is now recognized as an important hallmark of disease pathophysiology. Identifying the molecular mechanisms of cancer immune suppression in the laboratory is key to the design of more effective immunotherapeutic treatment strategies. We previously demonstrated that chronic lymphocytic leukemia (CLL) cells induce alterations in global gene expression profiles in patient CD4 and CD8 T cells, and a profound T cell immunological synapse formation defect that can be reversed with lenalidomide (J Clin Invest. 2005;115(7):1797-1805, and 2008;118(7):2427-2437). Here we used small interfering RNA (siRNA) with a 2-part functional screen to identify key CLL cell molecules inducing T cell immune suppression. siRNA treated tumor cells were cocultured in direct contact with healthy allogeneic T cells for 24 hours, T cells purified from coculture and used in cell conjugation immune synapse assays with superantigen-pulsed third party B cells as antigen-presenting cells (APCs). Confocal microscopy and image analysis software was used to quantify the mean area of T cell F-actin immune synapse formation events from each experimental cell population. Treatment of the CLL cell line MEC-1 with either TNFα, TGFβ, IL-10, or IL-6 siRNA identified no gain in subsequent CD3 T cell immune synapse function compared to control non-targeting siRNA or untreated CLL cells. However, CD200 or programmed death 1 (PD1) ligand 1 (PD-L1, CD274) siRNA treatment significantly enhanced (P < .01) subsequent T cell synapse formation events with APCs (comparable to positive control experiments blocking tumor cell:T cell direct contact with ICAM-1 siRNA, or primary coculture of T cells with allogeneic healthy donor B cells). Primary CLL patient cells (n=10) were treated with individual or pooled neutralizing antibodies, or siRNA, targeting PD-L1, CD200, or cytokines. This analysis revealed that counteracting the combined activity of PD-L1, CD200 and TGFβ exhibited the most pronounced repair of subsequent T cell synapse function compared to control treated tumor cells (P < .01). These data suggest that CLL-released cytokines such as TGFβ contribute to, but are not essential for the T cell synapse defect. We also identified that blocking the T cell receptors PD-1, CD200-R and TGFβ-R1 with neutralizing antibodies prevents CLL inhibitory signaling (P < .01) compared to isotype control IgG treated T cells in contact with tumor cells. We further show that knock-down of PD-L1, CD200 and TGFβ on ex vivo CLL cells prevents inhibitory CD4 and CD8 T cell synapse function compared to control siRNA (P < .01) using the Eμ-TCL1 mouse model of CLL. The addition of lenalidomide (1μM) in ex vivo CLL cell:T cell coculture assays significantly increased (P < .01) subsequent T cell synapse function compared to untreated vehicle control experiments. Flow cytometric analysis identified that lenalidomide down-regulates both CLL expressed PD-L1 and CD200 ligands, and T cell cognate receptor PD1 and CD200R expression during intercellular contact interactions. Moreover, subsequent effector T cell killing function was significantly enhanced (P < .05) following antibody blockade of CLL cell PD-L1 and CD200 with or without lenalidomide treatment during primary coculture with CD8 T cells. We are currently investigating the expression and activity of PD-L1, CD200, and other co-inhibitory molecules in CLL and other haematological and solid malignancies, using patient tissue microarray analysis and confocal co-localization analysis. This work is identifying common inhibitory ligands utilized by tumor cells to suppress T cell synapse function. These results provide important mechanistic insight into immune suppression in CLL and the action of lenalidomide, and identify co-inhibitory ligands as potential immunotherapeutic targets to repair T cell function. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

scholarly journals Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

2008 ◽  
Vol 205 (12) ◽  
pp. 2763-2779 ◽  
Author(s):  
R. Brad Jones ◽  
Lishomwa C. Ndhlovu ◽  
Jason D. Barbour ◽  
Prameet M. Sheth ◽  
Aashish R. Jha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Surface Expression ◽  
Cell Dysfunction ◽  
Cd38 Expression ◽  
Immunodeficiency Virus ◽  
T Cell Dysfunction ◽  
Novel Target ◽  
Hiv 1

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8+ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4+ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8+ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.

scholarly journals Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
J. Justin Milner ◽  
Clara Toma ◽  
Sara Quon ◽  
Kyla Omilusik ◽  
Nicole E. Scharping ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Small Molecule ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Cell Phenotype ◽  
Effector T Cell ◽  
Terminal Effector

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector–specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule–mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.

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