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Control of regulatory T cell development by the transcription factor Foxp3. Science , — Fontenot, J. Ivanov, I. Yu, D. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31 , — Nurieva, R. Bcl6 mediates the development of T follicular helper cells. Johnston, R. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.

Chan, S. What is a master regulator? Stem Cell. Oestreich, K. Master regulators or lineage-specifying? Wattler, S. A combined analysis of genomic and primary protein structure defines the phylogenetic relationship of new members if the T-box family. Genomics 48 , 24—33 Bollag, R. An ancient family of embryonically expressed mouse genes sharing a conserved protein motif with the T locus. Herrmann, B. Cloning of the T gene required in mesoderm formation in the mouse.

Naiche, L. T-box genes in vertebrate development. Papaioannou, V. The T-box gene family: emerging roles in development, stem cells and cancer. Development , — Flajnik, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures.

Bertrand, S. Evolutionary crossroads in developmental biology: amphioxus. Huang, G. The identification of lymphocyte-like cells and lymphoid-related genes in amphioxus indicates the twilight for the emergence of adaptive immune system. Horton, A. Evolution of developmental functions by the Eomesodermin, T-brain-1, Tbx21 subfamily of T-box genes: insights from amphioxus. Boehm, T. VLR-based adaptive immunity. Kang, J. Transcription factor networks directing the development, function, and evolution of innate lymphoid effectors.

Secombes, C. 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.

Characterization of T-bet and eomes in peripheral human immune cells. James J. Knox , University of Pennsylvania Gabriela L. Betts , University of Pennsylvania Laura M. McLane , University of Pennsylvania. This article has been peer reviewed.

The published version is available at DOI: The corrigendum can be found at DOI: 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. 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.

While this does not change our conclusions for the majority of the populations assessed in this study, B cells in particular show differences under these conditions. Specifically, permeabilization via the eBioscience FoxP3 transcription factor staining buffer set indicates that subpopulations of memory B cells express significantly higher levels of T-bet MFI compared to plasmablasts, and that plasmablasts express T-bet only at low levels.

Together, in combination with fluorescence-minus-one and isotype control studies, these new findings suggest that subsets memory B cells, not plasmablasts, express the highest levels of T-bet in the B cell compartment and plasmablasts express T-bet at a lower frequency than is reported in Figure 7.

Reduced frequencies of T-bet expression in plasmablasts indicate a specific role for T-bet at the memory B-cell stage of development, which may no longer be necessary after further differentiation to the plasmablast stage.

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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. Barnett, B. Cutting edge: B cell-intrinsic T-bet expression is required to control chronic viral infection. Knox, J. JCI Insight 2 , Chang, L. Viral Hepat. Kurktschiev, P. Hersperger, A. Ribeiro-dos-Santos, P. Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T cell differentiation into cytolytic effectors.

Buggert, M. Marshall, H. Immunity 35 , — Darrah, P. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Paley, M. Hoffmann, M. Mackay, L. T-box transcription factors combine with the cytokines TGF-beta and IL to control tissue-resident memory T cell fate.

Immunity 43 , — Klarquist, J. Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis. Jameson, S. Diversity in T cell memory: an embarrassment of riches. Olson, J. Immunity 38 , — Snyder, C. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells.

Immunity 29 , — Chu, H. Bottcher, J. Gerlach, C. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Herndler-Brandstetter, D. Immunity 48 , — Diaz, Y. Dorfman, D. T-bet, a T cell-associated transcription factor, is expressed in a subset of B cell lymphoproliferative disorders.

Differential expression of T-bet, a T-box transcription factor required for Th1 T cell development, in peripheral T cell lymphomas. Dolfi, D. Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans. Sasaki, Y. Identification of a novel type 1 diabetes susceptibility gene. Svensson, A. Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. 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.

While members of this family are known to play diverse roles in various developmental processes 2 , 3 , the functions of T-bet and Eomes have been best described in the context of the mouse immune system. T-bet has been implicated in sustaining memory subsets 13 — 16 , however, T-bet levels decline as cells become more memory-like Eomesodermin was originally identified in Xenopus 18 , and has since been found in many other vertebrates, where it plays key roles in mesoderm formation and early gastrulation events 18 , In contrast to T-bet, Eomes expression increases as cells become more memory-like 10 , 14 , 16 , 17 and Eomes knockout mice are deficient in long-term memory formation and fail to undergo homeostatic renewal 14 , 16 , 22 highlighting its critical role for memory differentiation.

Recently, evidence has emerged in mice that T-bet and Eomes may function in the context of other cells of the immune system; however, few studies have described the expression of these factors in human non-thymocyte immune cells. Additionally, few studies have investigated the co-expression of these factors within different immune cell subsets. In this study, we sought to broadly characterize the resting expression patterns of T-bet and Eomes in the context of a number of immune cells from normal human donors and to provide direct comparative data with identical optimal experimental conditions and cell sources to serve as a reference for future studies on these transcription factors in human lymphocytes.

Using multiparametric flow cytometry, our results reveal some parallels between human and mouse models, however, we find key differences in specific cell subsets suggesting the role of these factors might not be identical in mouse and humans. Flow cytometry analysis was performed as previously described 10 using PBMCs from at least eight normal donors. Where appropriate, statistical analyses were performed using GraphPad Prism software Version 5. While a fair amount is known about the relationship between T-bet and Eomes and the individual memory markers, the breakdown of their combined expression is not well defined.

Each symbol represents an individual donor. The line in the box represents the median value. F Co-expression of T-bet and Eomes within each memory subset is shown. T-regulatory cells function to suppress immune responses from other cell types to prevent hyperactivity or autoimmune disease.

T reg cells have been reported to upregulate T-bet in vivo during type-1 inflammatory responses 31 ; however, little is known about T-bet in circulating human T reg cells. Eomes expression was not detected in circulating T reg cells data not shown. Taken together, these data indicate that neither T-bet nor Eomes likely contribute to resting human T reg function. A representative donor is shown. T-cells are dependent upon IL-7 signaling for survival 32 — T-bet and Eomes expression within these cells from a representative donor is shown.

D Graphical representation of the mean frequency of T-bet hi gray and T-bet lo white expression in these populations is shown. G The frequency of T-bet and Eomes co-expression within each cell population is shown. In mice, T-bet and Eomes modulate many NK cell effector functions, including cytotoxicity and cytokine production 21 , Additionally, their expression is crucial for murine NK developmental regulation where they cooperate to influence several key developmental checkpoints T-bet and Eomes have been highly studied in mouse models, but there are few studies investigating the expression patterns of T-bet and Eomes within human NK cell populations; therefore, we next assessed T-bet and Eomes in human NK subsets.

Conversely, the T-bet lo population was significantly larger in CD56 bright cells white bars. Taken together, these data suggest that there may be an association between T-bet expression levels and functional capacity in NK cells: CD56 dim NK cells highly express T-bet and are highly cytotoxic, while poorly cytotoxic CD56 bright NK cells express less T-bet and function mainly to produce cytokines A Gating strategy for identifying NK cell subsets. Each symbol represents and individual donor.

C Box and whisker graphical representation of the frequency of T-bet hi gray and T-bet lo white expression for each NK population is shown. D The frequency of Eomes-expressing NK cells is shown. F Frequency of T-bet and Eomes co-expression within each subset. Taken together, these results suggest that while T-bet and Eomes likely play complementary or cooperative roles in the majority of NK cells, there may be distinct subpopulations of NK cells where T-bet and Eomes differentially regulate NK cell function.

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 Additionally, there is evidence to suggest that expression of T-bet in B-cells is necessary for clearance of gHV68, a murine herpes virus While it is appreciated that T-bet is necessary for appropriate B-cell function and antibody responses in mice, T-bet expression is not well-characterized in human B-cells.

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.

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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 [12] , [16].

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 [33].

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 [50]. 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 [56]. This hypothesis is supported by the fact that chronically high antigen levels cause T cell exhaustion during chronic viral infections [57]. 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. Figure 1.

Figure 2. Figure 3. Figure 4. Increased expression of inhibitory receptors and Eomes is traced to a transitional memory phenotype We further traced the expression of the inhibitory receptors to diverse memory phenotypes using CD45RO, CD27 and CCR7 in the untreated HIV-infected subjects. Figure 5. Figure 6. Supporting Information. Figure S1. Figure S2. Figure S3. Figure S4. Figure S5. Figure S6. Figure S7. Table S1. References 1. The Journal of experimental medicine — View Article Google Scholar 2.

Nature immunology 6: — View Article Google Scholar 3. Science — 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.