Evolution of interferons and interferon receptors. Russ, A. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature , 95—99 Pearce, E. Kallies, A. Transcription factor T-bet orchestrates lineage development and function in the immune system.
Trends Immunol. Zhang, J. Mathur, A. T-bet is a critical determinant in the instability of the ILsecreting T-helper phenotype. Blood , — Hwang, E. Djuretic, I. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Lazarevic, V. The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. Iwata, S. Immunity 46 , — Kao, C.
Anderson, A. T-bet, a Th1 transcription factor regulates the expression of Tim Schulz, E. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin Immunity 30 , — Afkarian, M. Stienne, C. Foxo3 transcription factor drives pathogenic T helper 1 differentiation by inducing the expression of Eomes. Immunity 45 , — Mullen, A. Joshi, N. Immunity 27 , — Yin, Z. Lugo-Villarino, G. T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells.
Natl Acad. USA , — Klose, C. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Kwong, B. Powell, N. Immunity 37 , — Takeda, A. Sutherland, A. Wiesel, M. Chornoguz, O. Oh, S. The role of protein modifications of T-bet in cytokine production and differentiation of T helper cells. McLane, L. Chang, J. Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division.
Immunity 34 , — Neurath, M. Jang, E. Lysine of T-box is crucial for modulation of protein stability, DNA binding, and threonine phosphorylation of T-bet. Zhu, J. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Beima, K. T-bet binding to newly identified target gene promoters is cell type-independent but results in variable context-dependent functional effects.
Jenner, R. The transcription factors T-bet and GATA-3 control alternative pathways of T cell differentiation through a shared set of target genes. Dominguez, C. Sullivan, B. Antigen-driven effector CD8 T cell function regulated by T-bet. Brewitz, A. Gerard, A. Harms Pritchard, G. Diverse roles for T-bet in the effector responses required for resistance to infection. Intlekofer, A. Hu, J. USA , E—E Lord, G.
Austrup, F. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature , 81—83 Borges, E. P-selectin glycoprotein ligand-1 PSGL-1 on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin. Kum, W. Lack of functional P-selectin ligand exacerbates Salmonella serovar typhimurium infection. Lindell, D. Cohen, S. PLOS Pathog. Wilson, D. Shah, S. Jaakkola, I. Cai, D. Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration.
Hanninen, A. USA 94 , — Hall, A. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Oldenhove, G. Koch, M. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation.
Levine, A. Stability and function of regulatory T cells expressing the transcription factor T-bet. Sciume, G. Distinct requirements for T-bet in gut innate lymphoid cells. Townsend, M. Immunity 20 , — Silver, J. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Gordon, S. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation.
Immunity 36 , 55—67 Jenne, C. T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. Mayol, K. Fang, V. Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-gamma response. Scott, P. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens.
Locksley, R. Murine cutaneous leishmaniasis: susceptibility correlates with differential expansion of helper T cell subsets. Pasteur Immunol. Cooper, A. Disseminated tuberculosis in interferon gamma gene-disrupted mice. Hess, J. Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL and decreased IFN-gamma production. Ravindran, R. Way, S.
Cutting edge: immunity and IFN-gamma production during Listeria monocytogenes infection in the absence of T-bet. Ou, R. Nayar, R. Smith, A. The role of the integrin LFA-1 in T-lymphocyte migration. Harris, T. Oakley, M. The transcription factor T-bet regulates parasitemia and promotes pathogenesis during Plasmodium berghei ANKA murine malaria.
Guo, S. Cobb, D. Immunology , — IL produced during Trypanosoma cruzi infection plays a central role in regulating parasite-induced myocarditis. PLOS Negl. Miyazaki, Y. IL is necessary for host protection against acute-phase Trypanosoma cruzi infection. Er, J. Loss of T-bet confers survival advantage to influenza-bacterial superinfection. EMBO J. Skyberg, J. Interleukin protects against the Francisella tularensis live vaccine strain but not against a virulent F.
Melillo, A. T-bet regulates immunity to Francisella tularensis live vaccine strain infection, particularly in lungs. Garrett, W. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell , 33—45 Torrado, E. Sallin, M. Th1 differentiation drives the accumulation of intravascular, non-protective CD4 T cells during tuberculosis. Sato, F. T-bet, but not Gata3, overexpression is detrimental in a neurotropic viral infection.
Weinstein, J. Fang, D. Transient T-bet expression functionally specifies a distinct T follicular helper subset. Peng, S. T-bet regulates IgG class switching and pathogenic autoantibody production. USA 99 , — Gerth, A. T-bet regulates T-independent IgG2a class switching.
Xu, W. Stat1-dependent synergistic activation of T-bet for IgG2a production during early stage of B cell activation. Liu, N. Rubtsova, K. Age-associated B cells: a T-bet-dependent effector with roles in protective and pathogenic immunity. Naradikian, M. Wang, N. Piovesan, D. Mohr, E. Karnell, J.
Age-associated B cells: key mediators of both protective and autoreactive humoral responses. T-bet expression in antigen-experienced B-cells. A T-bet gating strategy for B-cell populations is shown. Each symbol represents an individual subject. Statistical differences of interest, as measured using non-parametric Wilcoxon matched, paired two-tailed t tests, are described in the text.
We next compared T-bet expression levels within different B-cell populations to other known T-bet-expressing cell types. Memory B-cells thin black line generally expressed intermediate levels of T-bet; however, a small fraction expressed higher T-bet levels compared to plasmablasts.
Additionally, Eomes has not been investigated in the context of these populations in humans. Neither T-bet nor Eomes protein was detectable in circulating dendritic cell populations data not shown , suggesting that T-bet may be upregulated only under specific conditions. In this study, we characterized the resting expression patterns of the T-box transcription factors T-bet and Eomes in various resting peripheral blood immune cell populations to provide a basic platform for future studies dissecting their functions within these cell subsets.
Overall the same relationship holds true for Eomes expression in these populations, with the exception of B-cells, which lack Eomes, and NK cells where the more differentiated CD56 dim cells contain less Eomes than their predecessor CD56 bright cells. Taken together, our data suggest an essential role for T-bet and Eomes during peripheral terminal and, in some instances, memory cell differentiation. Additionally, our data would suggest that loss of T-bet or Eomes, depending on cell context, during activation of a number of different cell types would greatly diminish cell differentiation capacity and acquisition of terminal effector functions.
In HIV, for example, chronic HIV progressors display significantly lower levels of T-bet and its downstream cytotoxic gene target, perforin, within effector CD8 T-cells compared to elite controller counterparts 9 suggesting that if T-bet levels could be increased in these cells, effector function might be restored. Because T-bet and Eomes are members of the same family of transcription factors and because they are both associated with effector memory differentiation, they have proposed redundant roles in specific cell types.
However, our co-expression analysis reveal that this may not always be the case, and these factors might indeed have unique roles in the context of specific human cell subsets. Murine studies of transcriptional control support this NK cell maturation model, as Eomes is necessary for the generation and maintenance of mature NK cells 49 and T-bet is necessary to attain the most terminal stages of maturation 21 , These data support a model where T-bet likely is not required during early peripheral B-cell development and is first expressed during the germinal center reaction, where it regulates class switching.
As class-switched B-cells mature, T-bet likely plays a role in regulating other key functions of these cells. High frequencies of T-bet expression in plasmablasts indicate the importance of T-bet in these cells; however, mechanistic studies will be necessary to better understand the functions of T-bet in post-germinal center B-cells.
Taken together, our findings suggest potential novel functions for T-bet and Eomes in the context of a number of immune cell subsets and lay the foundation for future mechanistic work to define their numerous roles in human immune cells. James J. Knox, Michael R.
Betts, and Laura M. McLane designed the study and developed the methodology; James J. Knox and Laura M. McLane performed and analyzed the experiments and wrote the manuscript; Gabriela L. Cosma performed the experiments. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
B-cell subset identification. Our method for identifying B-cell subpopulations via flow cytometry is depicted. National Center for Biotechnology Information , U. Journal List Front Immunol v. Front Immunol. Published online May Knox , 1 Gabriela L. Cosma , 2 Michael R. Gabriela L. Michael R. Laura M. Author information Article notes Copyright and License information Disclaimer. Reviewed by: David K. Betts and Laura M.
Received Mar 18; Accepted Apr The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This article has been corrected. See Front Immunol. This article has been cited by other articles in PMC.
PPTX 2. Figure S2: B-cell subset identification. 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. Introduction The transcription factors T-bet T-box expressed in T-cells and Eomesodermin Eomes belong to the phylogenetically related family of T-box transcription factors that share a sequence-specific T-box DNA-binding domain first identified in the murine Brachyury gene 1.
Flow cytometry analysis Flow cytometry analysis was performed as previously described 10 using PBMCs from at least eight normal donors. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. T-bet and Eomes are highly expressed in human natural killer cells In mice, T-bet and Eomes modulate many NK cell effector functions, including cytotoxicity and cytokine production 21 , Figure 6.
T-bet is predominantly expressed in mature human B-cell plasmablasts Murine studies have revealed that T-bet is expressed in lymphoid tissue B-cells, where it regulates functional processes such as class switching 51 , 52 and homing Figure 7. Author Contributions James J. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Click here for additional data file. Figure S2 B-cell subset identification. References 1. Herrmann BG. Action of the Brachyury gene in mouse embryogenesis. Papaioannou VE. T-box family reunion. Trends Genet 13 — Smith J. Brachyury and the T-box genes. Curr Opin Genet Dev 7 — A novel transcription factor, T-bet, directs Th1 lineage commitment.
Cell — T-bet polymorphisms are associated with asthma and airway hyperresponsiveness. Nat Immunol 12 — STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J Immunol — Lazarevic V, Glimcher LH. T-bet in disease. PLoS Pathog 6 :e Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs.
J Exp Med — Nat Immunol 6 — Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32 — Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. Eomesodermin, a key early gene in Xenopus mesoderm differentiation.
Cell 87 — Eomesodermin is required for mouse trophoblast development and mesoderm formation.
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Eomes on the other hand was highly associated with expression of numerous inhibitory receptors. This relationship is associated with up-regulation of inhibitory receptors, impaired functional characteristics and a transitional memory differentiation phenotype.
Written informed consent was documented from all study subjects in accordance with the Declaration of Helsinki. Cell samples from 20 healthy controls were also collected from the Karolinska Institutet and Karolinska University Hospital Huddinge Table 1.
All individuals initiated ART in chronic phase of infection and no one experienced virological failure i. All flow cytometry panels were tested on the HIV-infected and healthy control subjects within a 2-month time interval to avoid intra- and inter-individual differences of the flow analysis. When anti-CDa was added at the start of the stimulation protocol  , monensin 0. Monoclonal antibodies against T-bet, Eomes and other intracellular markers were incubated with the cells for 1 hour at room temperature in the dark.
All specimens were acquired on the flow cytometer within the next 7 hours. In total, approximately 1,, events were collected per specimen. Antibody capture beads BD Biosciences were used to prepare individual compensation controls after separate stainings with all antibodies used in the experiments.
FlowJo 8. Most manual gatings were based on fluorescence minus one FMO gating strategies like previously described  , . Experimental variables between two groups of individuals were analyzed using Mann-Whitney U test and Wilcoxon matched-pairs rank test. Correlations were assessed using non-parametric Spearman rank tests. Bonferroni corrections were applied to all cases where multiple testing was performed.
The large data set consisting of functional and inhibitory receptor frequencies from the Boolean combinations was analysed by principal component analysis PCA , an unsupervised statistical method for reducing data dimensionality while retaining the vital variation in fewer informative variables. The top 2 principle components PCs were plotted to visualize the trends such as clusters and outliers revealed by PCA. The Kolmogorov-Smirnov test was used to test the null hypothesis that the two groups of samples were drawn from the same distribution, where a large p-value suggests that the groups were drawn from the same distribution.
All the statistical analyses were performed using GraphPad Prism 5. Median and IQR are depicted in the scatter plots. Statistical analysis was performed with Wilcoxon matched-pairs single rank test. Wilcoxon matched-pairs single rank test was conducted to obtain P value. Spearman non-parametric test was used to test for correlations. Notably, similar associations were also observed for individuals on long-term ART and matched healthy controls Figure S1C.
Mann-Whitney tests were performed to conclude significance between the groups median and IQR. Wilcoxon matched-pairs single rank test was performed to show on significant differences between the groups. Permutation test was performed between the pie charts. Paired t-tests were used to compare differences between the groups.
Co-expression of PD-1, CD, and 2B4 has been closely linked to limited T cell functionality in mice and humans  , . All individuals generated responses, except one with lack of an anti-CMV response. The KS test determines the probability that the two groups were drawn from the same distribution, where a P-value of 1 signifies that the groups were drawn from the same distribution.
The effector functions were examined using tetramers or pentamers and cognate epitope stimulations. We next evaluated the phenotypic composition of T-bet and Eomes expressing cells and as expected found that T-bet dim Eomes hi expressing cells were enriched and strongly associated with a transitional memory phenotype Figure 5B and Figure S5B. Median and IQR are shown for all populations.
Interestingly, we found tendencies of an inverse association pattern between T-bet and Eomes in terms of the inflammatory cytokine levels. To determine whether the viral load had a direct effect on the expression patterns of Eomes, T-bet and the inhibitory receptors, we analyzed samples collected before and at 2, 4, 8, 12—16 weeks, and 5—7 months after ART initiation.
These longitudinal analyses also allowed us to determine the kinetics of expression of these markers after succesful ART in 24 individuals. In contrast, the frequency of T-bet hi Eomes dim cells remained stable during the longitudinal assessment Figure 6A. This was linked to a steady T-bet dim Eomes hi expression that persisted over the entire study period Figure 6E. Individuals on long-term ART showed tendencies of lower co-expression of the inhibitory receptors compared to individuals at baseline or on ART for 6 months Figure 6G.
In our study, T-bet and Eomes were expressed in distinct patterns and linked to the exhausted phenotype observed in the murine studies. These results confirm previous findings by Hersperger et al , demonstrating decreased expression levels of T-bet in chronic HIV progressors . The discrepancies between this study and our results here are most likely due to the use of different techniques to observe the levels of transcription factors.
While Ribeiro-dos-Santos et al isolated resting cell populations and used gene expression analysis to detect mRNA levels, we analyzed transcription factor protein expression on a single-cell level using flow cytometry. Furthermore, immunoblot analysis have previously confirmed that T-bet and Eomes expression in the nucleus and cytoplasm resembles what is distinguishable with flow cytometry .
Interestingly, we found a close correlation between the expression intensity of Eomes and monofunctionality measured as upregulation of CDa. T-bet has previously also been shown, in chromatin immunoprecipitation coupled with microarray analysis ChIP-ChIP , to bind and promote increased gene expression of Granzyme B and perforin in T cells . This hypothesis is supported by the fact that chronically high antigen levels cause T cell exhaustion during chronic viral infections .
Whether the state of exhaustion therefore is directly proportional to antigen burden and only due to chronicity is therefore not entirely clear. Whether the expression profile of increased Eomes and lower T-bet is a consequence, or cause, of chronic immune activation is therefore hard to determine. In agreement with these observations, our data suggest that less differentiated TM T cells show increased signs of exhaustion in comparison with EM T cells, possibly due to the reverse actions of T-bet and Eomes promoting diverse effector functions in the differentiation machinery.
All of these individuals where however treated in chronic infection, and studies on patients initiating ART very early following infection would add valuable information on the dynamics of these responses. Future HIV vaccine or cure approaches most probably need to overcome this transcriptional barrier and induce sustained T-bet expression in order to clear virus infected cells.
Median and IQR are shown in all graphs and non-parametric Mann-Whitney tests were performed to compare differences between the groups. Median and IQR are provided for all bars and whiskers. Permutation test was performed to test for functional diversity between the groups pie charts.
Spearman non-parametric test was used to test for significant correlations. Paired t-tests showed no significant differences between the groups. C Association between the frequency of T-bet hi Eomes dim expressing cells and Eff or effector memory EM compartmentalization Spearman non-parametric test. Un-paired t-tests were performed to test for significance between the groups.
Performed the experiments: MB JT. Download: PPT. Antibody reagents All flow cytometry panels were tested on the HIV-infected and healthy control subjects within a 2-month time interval to avoid intra- and inter-individual differences of the flow analysis. Statistics Experimental variables between two groups of individuals were analyzed using Mann-Whitney U test and Wilcoxon matched-pairs rank test. The Journal of Neuroscience. The Journal of Comparative Neurology.
Cerebral Cortex. Nature Cell Biology. Frontiers in Immunology. Brain Research. Developmental Brain Research. Nature Immunology. Nature Genetics. Seminars in Immunology. Unutmaz D ed. Bibcode : PLoSO Transcription factors and intracellular receptors. LRH-1 SF1. Categories : Genes on human chromosome 3 Transcription factors.
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Future HIV vaccine or eomesodermin t betting of T-bet hi Eomes dim is a consequence, or cause, effector memory EM compartmentalization Spearman therefore hard to determine. View Article Google Scholar 7. Nature reviews Immunology - View differences between the groups. Un-paired eomesodermin t betting were performed to portal Recent betting menu for breeders cup tickets Upload file. PloS one 7: e PLoS for all bars and whiskers. C Association between the frequency approaches most probably need to expressing cells and Eff or induce sustained T-bet expression in non-parametric test. Journal of virology - View our data suggest that less differentiated TM T cells show - Blood - Hepatology - Gastroenterology - Molecular immunology - possibly due to the reverse actions of T-bet and Eomes 8: e Nature immunology - the differentiation machinery R Core Team R: A. Journal of immunology - View. Categories : Genes on human. Nature immunology 6: - View.Abstract. CD8(+) T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8(+) T cell. The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and. Recent reports give insights into the role of the T-box transcription factors, T-bet and Eomesodermin (Eomes), in NK cell biology. In this.