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Characterization of T-bet and eomes in peripheral human immune cells.

ABSTRACT: The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized. In this study, we used multiparametric flow cytometry to characterize T-bet and Eomes expression in major human blood cell subsets, including total CD4(+) and CD8(+) T-cells, ?? T-cells, invariant NKT cells, natural killer cells, B-cells, and dendritic cells. Our studies identified novel cell subsets that express T-bet and Eomes and raise implications for their possible functions in the context of other human immune cell subsets besides their well-known roles in T-cells.

SUBMITTER: Knox JJ

PROVIDER: S-EPMC4030168 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Characterization of T-bet and eomes in peripheral human immune cells.

Knox James J JJ Cosma Gabriela L GL Betts Michael R MR McLane Laura M LM

Frontiers in immunology 20140514

The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively u ...[more]

PMID: 24860576

Similar Datasets

T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells.

Project description:T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.

| S-EPMC8497824 | biostudies-literature

T-BET and EOMES sustain mature human NK cell identity and antitumor function.

Project description:Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-Seq revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET- and EOMES-deleted CD56bright NK cells acquired an innate lymphoid cell precursor-like (ILCP-like) profile with increased expression of the ILC-3-associated TFs RORC and AHR, revealing a role for T-box TFs in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity.

| S-EPMC10313375 | biostudies-literature

Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells.

Project description:EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.

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Eomes cannot replace its paralog T-bet during expansion and differentiation of CD8 effector T cells.

Project description:The two T-box transcription factors T-bet and Eomesodermin (Eomes) are important regulators of cytotoxic lymphocytes (CTLs), such as activated CD8 T cells, which are essential in the fight against intracellular pathogens and tumors. Both transcription factors share a great degree of homology based on sequence analysis and as a result exert partial functional redundancy during viral infection. However, the actual degree of redundancy between T-bet and Eomes remains a matter of debate and is further confounded by their distinct spatiotemporal expression pattern in activated CD8 T cells. To directly investigate the functional overlap of these transcription factors, we generated a new mouse model in which Eomes expression is under the transcriptional control of the endogenous Tbx21 (encoding for T-bet) locus. Applying this model, we demonstrate that the induction of Eomes in lieu of T-bet cannot rescue T-bet deficiency in CD8 T cells during acute lymphocytic choriomeningitis virus (LCMV) infection. We found that the expression of Eomes instead of T-bet was not sufficient for early cell expansion or effector cell differentiation. Finally, we show that imposed expression of Eomes after acute viral infection promotes some features of exhaustion but must act in concert with other factors during chronic viral infection to establish all hallmarks of exhaustion. In summary, our results clearly underline the importance of T-bet in guiding canonical CTL development during acute viral infections.

| S-EPMC7546498 | biostudies-literature

T-bet:Eomes balance, effector function, and proliferation of cytomegalovirus-specific CD8+ T cells during primary infection differentiates the capacity for durable immune control.

Project description:CMV remains an important opportunistic pathogen in solid organ transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor+/recipient-; D+R-) are at high-risk for active CMV infection and increased mortality, however the immune correlates of viral control remain incompletely understood. We prospectively studied 23 D+R- LTRs during primary CMV infection to determine whether acute CD8(+) T cell parameters differentiated the capacity for viral control in early chronic infection. T-box transcription factors expression patterns of T-bet > Eomesodermin (Eomes) differentiated LTR controllers from viremic relapsers and reciprocally correlated with granzyme B loading, and CMV phosphoprotein 65 (pp65)-specific CD8(+)IFN-γ(+) and CD107a(+) frequencies. LTR relapsers demonstrated reduced CD8(+)Ki67(+) cells ex vivo and substantially impaired CD8(+)pp65-specific in vitro proliferative responses at 6 d, with concomitantly lower pp65-specific CD4(+)IL-2(+) frequencies, as compared with LTR controllers. However, CMV-specific in vitro proliferative responses could be significantly rescued, most effectively with pp65 Ag and exogenous IL-2, resulting in an increased T-bet:Eomes balance, and enhanced effector function. Using class I CMV tetramers, we observed similar frequencies between relapsers and controllers, although reduced T-bet:Eomes balance in tetramer(+) cells from relapsers, along with impaired CD8(+) effector responses to tetramer-peptide restimulation. Taken together, these data show impaired CMV-specific CD8(+) effector responses is not for complete lack of CMV-specific cells but rather underscores the importance of the T-bet:Eomes balance, with CMV-specific proliferation a key factor driving early T-bet expression and effector function in CD8(+) T cells during primary infection and differentiating the capacity of high-risk LTRs to establish immune control during early chronic infection.

| S-EPMC4239205 | biostudies-literature

T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells.

Project description:Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62L(high)CD44(low) Sca-1(+) T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells.

| S-EPMC3694876 | biostudies-literature

T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection.

Project description:CD8(+) T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8(+) T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8(+) T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8(+) T cells was elevated in chronically infected individuals and highly associated with a T-bet(dim)Eomes(hi) expressional profile. Interestingly, both resting and activated HIV-specific CD8(+) T cells in chronic infection were almost exclusively T-bet(dim)Eomes(hi) cells, while CMV-specific CD8(+) T cells displayed a balanced expression pattern of T-bet and Eomes. The T-bet(dim)Eomes(hi) virus-specific CD8(+) T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8(+) T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8(+) T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8(+) T cells to control the viral replication post-ART cessation.

| S-EPMC4102564 | biostudies-literature

Identification of a Porcine Liver Eomes<sup>high</sup>T-bet<sup>low</sup> NK Cell Subset That Resembles Human Liver Resident NK Cells.

Project description:Natural killer (NK) cells are cells of the innate immunity and play an important role in the defense against viral infections and cancer, but also contribute to shaping adaptive immune responses. Long-lived tissue-resident NK cells have been described in man and mouse, particularly in the liver, contributing to the idea that the functional palette of NK cells may be broader than originally thought, and may include memory-like responses and maintaining tissue homeostasis. Remarkably, liver resident (lr)NK cells in man and mouse show substantial species-specific differences, in particular reverse expression patterns of the T-box transcription factors Eomesodermin (Eomes) and T-bet (EomeshighT-betlow in man and vice versa in mouse). In pig, compared to blood NK cells which are CD3-CD8αhigh cells, the porcine liver contains an abundant additional CD3-CD8αdim NK cell subpopulation. In the current study, we show that this porcine CD3-CD8αdim liver NK population is highly similar to its human lrNK counterpart and therefore different from mouse lrNK cells. Like human lrNK cells, this porcine NK cell population shows an EomeshighT-betlow expression pattern. In addition, like its human counterpart, the porcine liver NK population is CD49e- and CXCR6+. Furthermore, the porcine EomeshighT-betlow liver NK cell population is able to produce IFN-γ upon IL-2/12/18 stimulation but lacks the ability to kill K562 or pseudorabies virus-infected target cells, although limited degranulation could be observed upon incubation with K562 cells or upon CD16 crosslinking. All together, these results show that porcine EomeshighT-betlow NK cells in the liver strongly resemble human lrNK cells, and therefore indicate that the pig may represent a unique model to study the function of these lrNK cells in health and disease.

| S-EPMC6836759 | biostudies-literature

Differential localization of T-bet and Eomes in CD8 T cell memory populations.

Project description:In mice, two T-box transcription factors, T-box expressed in T cells (T-bet) and eomesodermin (Eomes), drive the differentiation of CD8 T cell lineages; however, little is known regarding their role in human CD8 T cell differentiation. In this study, we characterized T-bet and Eomes expression and localization within human CD8 memory T cell populations. We find that T-bet and Eomes are broadly expressed in human memory CD8 T cells, with increasing levels of T-bet and Eomes strongly correlating with differentiation from central memory to effector memory and effector subpopulations. In resting T cells, T-bet levels directly correlate to subcellular localization, with a higher propensity for nuclear expression of T-bet within T-bet(hi) cells and predominantly cytoplasmic expression in T-bet(lo) cells. In addition, Eomes is also localized to either the nucleus or the cytoplasm. Upon TCR stimulation, the percentage of T cells that express T-bet dramatically increases, whereas the percentage of cells expressing Eomes remains largely unchanged across all memory populations. Of interest, T-bet, but not Eomes, relocalizes to the nucleus in the majority of cells across all populations within 24 h post stimulation. These data indicate that T-bet and Eomes are likely regulated at the level of subcellular localization, potentially via different mechanisms. Together, these findings suggest a novel model for CD8 T cell differentiation in humans that is based on the localization of T-bet and Eomes.

| S-EPMC3608800 | biostudies-literature

Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells.

Project description:The transcription factors T-bet and Eomesodermin (Eomes) regulate CD8 T cell exhaustion through undefined mechanisms. Here, we show that the subcellular localization of T-bet and Eomes dictate their regulatory activity in exhausted T cells (TEXs). TEXs had a higher ratio of nuclear Eomes:T-bet than memory T cells (TMEMs) during chronic lymphocytic choriomeningitis virus (LCMV) infection in preclinical cancer models and in human tumors. Biochemically, T-bet and Eomes compete for the same DNA sequences, including the Pdcd1 T-box. High nuclear T-bet strongly represses Pdcd1 transcription in TMEM, whereas low nuclear T-bet in TEX leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in TEXs increases nuclear T-bet, restoring stronger repression of Pdcd1, and driving T-bet-associated gene expression programs of chemotaxis, homing, and activation. These data identify a mechanism whereby the T-bet-Eomes axis regulates exhaustion through their nuclear localization, providing insights into how these transcription factors regulate TEX biology.

| S-EPMC8195461 | biostudies-literature

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