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Steven L Reiner

Publications and source records attributed to Steven L Reiner.

At least 19 recordsLinked to original sources
PubMed2006

Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation.

Cytokines are critical determinants for specification of lineage-defining transcription factors of CD4+ T cell subsets. Little is known, however, about how cytokines regulate expression of T-bet and eomesodermin (Eomes) in effector and memory CD8+ T cells. We now report that IL-12, a signature of cell-mediated immunity, represses Eomes while positively regulating T-bet in effector CD8+ T cells during infection with Listeria monocytogenes. After resolution of infection and abatement of IL-12 signaling, Eomes expression rises whereas T-bet expression declines in memory CD8+ T cells. Eomes becomes derepressed in effector cells by ablation of IL-12 signaling. In the absence of IL-12, the dynamics of clonal expansion and contraction are also perturbed. Together, these results reveal how a pathogen-associated signal, such as IL-12, could act as a switch, regulating appropriate clonal growth and decline while, in parallel, shaping a unique pattern of fate-determining transcription factors.

Animals↗
PubMed2006

IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomesodermin expression.

Exposure of naive Th cell precursors (Thp) to IL-21 inhibits IFN-gamma production from developing Th1 cells. The inhibition of IFN-gamma seen in IL-21-treated Thp cells is specific as the expression of other Th1 cytokines is unaffected. Recently, it has been reported that Eomesodermin (Eomes), a member of the T-box gene family, is expressed in developing CD8+ T cells and plays an important role in regulating IFN-gamma production and cytolytic effector function. In this study, we show that Eomes mRNA and protein are also expressed in developing Th1 cells, and exposure of naive Thp cells to IL-21 results in a decrease in Eomes expression. Moreover, the repression of Eomes expression by IL-21 is not due to an indirect effect of IL-21 on the expression of IFN-gamma or STAT4 and is independent of STAT1 and T-bet expression. Finally, we show that ectopic expression of Eomes prevents the inhibition of IFN-gamma production from IL-21-treated Thp cells. Taken together, these results demonstrate that Eomes plays a role in regulating IFN-gamma production in CD4+ T cells and IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomes expression.

Animals↗
PubMed2006

Antigen-experienced T cells limit the priming of naive T cells during infection with Leishmania major.

One mechanism to control immune responses following infection is to rapidly down-regulate Ag presentation, which has been observed in acute viral and bacterial infections. In this study, we describe experiments designed to address whether Ag presentation is decreased after an initial response to Leishmania major. Naive alphabeta-Leishmania-specific (ABLE) TCR transgenic T cells were adoptively transferred into mice at various times after L. major infection to determine the duration of presentation of parasite-derived Ags. ABLE T cells responded vigorously at the initiation of infection, but the ability to prime these cells quickly diminished, independent of IL-10, regulatory T cells, or Ag load. However, Ag-experienced clonal and polyclonal T cell populations could respond, indicating that the diminution in naive ABLE cell responses was not due to lack of Ag presentation. Because naive T cell priming could be restored by removal of the endogenous T cell population, or adoptive transfer of Ag-pulsed dendritic cells, it appears that T cells that have previously encountered Ag during infection compete with naive Ag-specific T cells. These results suggest that during L. major infection Ag-experienced T cells, rather than naive T cells, may be primarily responsible for sustaining the immune response.

Adoptive Transfer↗
PubMed2006

T-bet down-modulation in tolerized Th1 effector CD4 cells confers a TCR-distal signaling defect that selectively impairs IFN-gamma expression.

When Th1 effector CD4 cells encounter tolerizing Ag in vivo, their capacity to express the effector cytokines IFN-gamma and TNF-alpha is lost more rapidly than noneffector functions such as IL-2 production and proliferation. To localize the relevant intracellular signaling defects, cytokine expression was compared following restimulation with Ag vs agents that bypass TCR-proximal signaling. IFN-gamma and TNF-alpha expression were both partially rescued when TCR-proximal signaling was bypassed, indicating that both TCR-proximal and -distal signaling defects impair the expression of these two effector cytokines. In contrast, bypassing TCR-proximal signaling fully rescued IL-2 expression. T-bet, a transcription and chromatin remodeling factor that is required to direct the differentiation of naive CD4 cells into IFN-gamma-expressing Th1 effectors, was partially down-modulated in tolerized Th1 effectors. Enforcing T-bet expression during tolerization selectively rescued the ability to express IFN-gamma, but not TNF-alpha. Conversely, expression of a dominant-negative T-bet in Th1 effectors selectively impaired the ability to express IFN-gamma, but not TNF-alpha. Analysis of histone acetylation at the IFN-gamma promoter further suggested that down-modulation of T-bet expression during Th1 effector CD4 cell tolerization does not impair IFN-gamma expression potential through alterations in chromatin structure.

Adoptive Transfer↗
PubMed2006

The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells.

The Tec family tyrosine kinases, Itk and Rlk, are expressed in thymocytes and peripheral T cells and regulate thresholds of T cell receptor signaling. Yet little is known about the specific role of Itk- and Rlk-dependent signals in CD8(+) T cell maturation. We show here that Itk(-/-) and Rlk(-/-)Itk(-/-) mice were nearly devoid of conventional CD8(+) T cells and, instead, contained a large population of CD8(+) T cells that bear striking similarity to lineages of innate lymphocytes. Itk(-/-) and Rlk(-/-)Itk(-/-) CD8(+) thymocytes and T cells were CD44(hi), CD122(+), and NK1.1(+); were able to produce interferon-gamma directly ex vivo; and were dependent on interleukin-15. Itk(-/-) and Rlk(-/-)Itk(-/-) CD8(+) thymocytes expressed abundant transcripts for the T box transcription factor, eomesodermin, correlating with their phenotype and function. These data indicate a critical role for Itk and Rlk in conventional CD8(+) T cell development in the thymus.

Animals↗
PubMed2006

Not-so-great expectations: re-assessing the essence of T-cell memory.

We are often taught that secondary, or memory, responses by lymphocytes are more vigorous than primary responses. An expectation commonly associated with this notion is that the initial encounter with a pathogen should result in immunity to re-infection. Although this outcome is sometimes the case, it is not universally true. In this review, we propose a unified model of T-cell memory to explain the apparent successes and failures of eliciting vaccine-like protection from prior encounters with pathogens. We speculate that memory T cells arise as an invariant consequence of clonal selection during an immune response. The quality of memory T cells, however, seems to vary in the degree to which they have acquired effector characteristics and, thus, their ability to confer immunity to re-infection. Although not all memory T cells possess the embellished attributes of fully developed effector cells, they all seem to share the rudimentary quality of preserving an antigen specificity that has proven itself useful. We suggest that the ability to maintain the integrity of the T-cell repertoire, more than establishing immunity to re-infection, may represent the fundamental form of memory for the adaptive immune system.

Animals↗
PubMed2005

Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin.

Two seemingly unrelated hallmarks of memory CD8(+) T cells are cytokine-driven proliferative renewal after pathogen clearance and a latent effector program in anticipation of rechallenge. Memory CD8(+) T cells and natural killer cells share cytotoxic potential and dependence on the growth factor interleukin 15. We now show that mice with compound mutations of the genes encoding the transcription factors T-bet and eomesodermin were nearly devoid of several lineages dependent on interleukin 15, including memory CD8(+) T cells and mature natural killer cells, and that their cells had defective cytotoxic effector programming. Moreover, T-bet and eomesodermin were responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness. Therefore, these key transcription factors link the long-term renewal of memory CD8(+) T cells to their characteristic effector potency.

Animals↗
PubMed2005

Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity.

Immunity often depends on proper cell fate choice by helper T lymphocytes. A naive cell, with minimal expression of IFN-gamma and IL-4, must give rise to progeny expressing high levels of either one, but not both, of those cytokines to defend against protozoan and helminthic pathogens, respectively. In the present study, we show that inactivation of the Mbd2 gene, which links DNA methylation and repressed chromatin, results in enhanced resistance to the protozoan parasite Leishmania major but impaired immunity to the intestinal helminth Trichuris muris. Helper T cells from methyl CpG-binding domain protein-2-deficient mice exhibit exuberant patterns of cytokine expression despite appropriate silencing of genes encoding the lineage-specifying factors T-bet and GATA-3. These results suggest that gene silencing can facilitate the ability of a progenitor cell to give rise to appropriately differentiated daughter cells in vivo. These findings also point to novel pathways that could participate in genetic control of resistance to infection and autoimmunity.

Animals↗
PubMed2005

Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression.

The stability of helper T cell fates is not well understood. Using conditional introduction of dominant-negative factors, we now show that T-bet and GATA-3 are far more critical in establishment than maintenance of IFN-gamma and IL-4 activity during Th1 and Th2 maturation, respectively. We also show that a genetic interaction between T-bet and its target Hlx seems to be required for Th1 maturation, but that Hlx may also be dispensable for maintenance of a transcriptionally permissive ifng gene. In parallel to progressive activator independence in the permissive lineage, the ifng gene becomes more recalcitrant to switching as the forbidden lineage matures. T-bet plus Hlx can disrupt ifng silencing when introduced into developing Th2 cells, but they fail to perturb ifng silencing in mature Th2 cells. In contrast, a hypermorphic allele of T-bet can reverse silencing of the ifng gene in mature Th2 cells. These results suggest that signature gene activity of helper T cells is initially plastic but later becomes epigenetically fixed and offer an initial strategy for inducing mature cells to switch their fate.

Animals↗
PubMed2005

Epigenetic control in the immune response.

Helper T cells engaged in an immune response confront a prevalent challenge for developmentally regulated gene expression: How does a cell give rise to daughter cells with different fates? Additionally, lymphocyte function is intimately associated with the processes of cell division and migration. This imposes an additional burden for daughter cells, to remember inductive events from which they are temporally and spatially removed. An emerging view is that helper T cells use epigenetic mechanisms tied to the structure of chromatin and its covalent modifications to achieve at least two important features of their programmed gene expression. Epigenetic effects organize the ability of signal transduction pathways to generate a restricted set of progeny from a multi-potent progenitor. In addition, epigenetic effects seem to allow dividing cells to memorize, or imprint, signaling events that occurred earlier in their development. Beyond helper T cells, the use of epigenetic effects is emerging as a common strategy in development and function of the mammalian immune system, suggesting that epigenetic effects may play a more prominent role in metazoan cell differentiation than previously appreciated. Lymphocytes are, thus, becoming a tractable system for genetic and biochemical dissection of the ways in which the genome is embedded with regulatory information to achieve developmental complexity.

Animals↗
PubMed2004

Expansion and function of CD8+ T cells expressing Ly49 inhibitory receptors specific for MHC class I molecules.

MHC class I-specific Ly49 inhibitory receptors regulate NK cell activation, thereby preventing autologous damage to normal cells. Ly49 receptors are also expressed on a subset of CD8+ T cells whose origin and function remain unknown. We report here that, despite their phenotypic and cytolytic similarities, Ly49+CD8+ T cells and conventional Ly49-CD44high memory-phenotype CD8+ T cells present strikingly distinct features. First, under steady state conditions Ly49+CD8+ T cells are poor cytokine producers (TNF-alpha and IFN-gamma) upon TCR triggering. Second, Ly49+CD8+ T cells are not induced upon various settings of Ag immunization or microbial challenge. However, Ly49 can be induced on a fraction of self-specific CD8+ T cells if CD4+ T cells are present. Finally, the size of the Ly49+CD8+ T cell subset is selectively reduced in the absence of STAT1. These results indicate that Ly49 expression is associated with a differentiation program of cytolytic CD8+ T cells triggered upon chronic antigenic exposure. They further suggest that the size of the Ly49+CD8+ T cell subset marks a history of CD8+ T cell activation that might preferentially result from endogenous inducers of inflammation rather than from microbial infections.

Animals↗
PubMed2004

Cutting Edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter.

The ability of NK and T cells to produce IFN-gamma is critical for resistance to numerous intracellular pathogens but the kinetics of these responses differ. Consistent with this is a requirement for naive T cells to become activated and undergo proliferation-dependent epigenetic changes to the IFN-gamma locus that allow them to produce IFN-gamma. The data presented here reveal that unlike T cells, murine NK cells produce IFN-gamma under conditions of short-term cytokine stimulation, and these events are independent of proliferation and cell cycle progression. Furthermore, analysis of the IFN-gamma locus in NK cells reveals that this locus is constitutively demethylated. The finding that NK cells do not need to remodel the IFN-gamma locus to produce IFN-gamma, either because they do not exhibit epigenetic repression or they have undergone prior remodeling during development, provides a molecular basis for the innate and adaptive regulation of the production of this cytokine.

Animals↗
PubMed2004

STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis.

The production of IFN-gamma by T cells and the ability of this cytokine to activate the transcription factor STAT1 are implicated in the activation of antimicrobial mechanisms required for resistance to intracellular pathogens. In addition, recent studies have suggested that the ability of STAT1 to inhibit the activation of STAT4 prevents the development of Th1 responses. However, other studies suggest that STAT1 is required to enhance the expression of T-bet, a transcription factor that promotes Th1 responses. To address the role of STAT1 in resistance to T. gondii, Stat1-/- mice were infected with this pathogen, and their response to infection was assessed. Although Stat1-/- mice produced normal serum levels of IL-12 and IFN-gamma, these mice were unable to control parasite replication and rapidly succumbed to this infection. Susceptibility to toxoplasmosis was associated with an inability to up-regulate MHC expression on macrophages, defects in NO production, and the inability to up-regulate some of the IFN-inducible GTPase family of proteins, molecules associated with antitoxoplasma activity. Analysis of T cell responses revealed that STAT1 was not required for the development of a Th1 response, but was required for the infection-induced up-regulation of T-bet. Together these studies suggest that during toxoplasmosis the major role of STAT1 is not in the development of protective T cell responses, but, rather, STAT1 is important in the development of antimicrobial effector mechanisms.

Animals↗
PubMed2004

Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation.

To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a gamma-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-gamma during T helper cell differentiation. Instead, IFN-gamma was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves.

Animals↗
PubMed2003

Control of effector CD8+ T cell function by the transcription factor Eomesodermin.

Activated CD8+ T cells play a critical role in host defense against viruses, intracellular microbes, and tumors. It is not clear if a key regulatory transcription factor unites the effector functions of CD8+ T cells. We now show that Eomesodermin (Eomes), a paralogue of T-bet, is induced in effector CD8+ T cells in vitro and in vivo. Ectopic expression of Eomes was sufficient to invoke attributes of effector CD8+ T cells, including interferon-gamma (IFN-gamma), perforin, and granzyme B. Loss-of-function analysis suggests Eomes may also be necessary for full effector differentiation of CD8+ T cells. We suggest that Eomesodermin is likely to complement the actions of T-bet and act as a key regulatory gene in the development of cell-mediated immunity.

Amino Acid Sequence↗
PubMed2003

Immunity and the animation of the genome.

Expression of genes in the right place at the right time is fundamental to all of life. The ontogeny of effector and memory T cells is a robust example of this important principle. Although lymphocytes represent a late addition in animal evolution, they are serving as an exceptional model system to unlock the mysteries surrounding the way in which the genome is animated. It will be speculated here that further insight into fundamental principles of genome function may arise from study of immunity. Likewise, such information may be key to understanding and altering immunobiology.

Animals↗
PubMed2003

Helper T cell differentiation and the problem of cellular inheritance.

The quality of the helper T cell response against antigen can determine the outcomes of infectious, inflammatory, and autoimmune diseases. Mature Th1 and Th2 cell subsets are thought to arise from a common naive progenitor. In these precursor cells, effector cytokine genes appear to exist in a restrictive structure, which is determined by methylation of cytosine bases and higher-order structure of chromatin. The restrictive gene structures appear to be plastic, giving way to more active structures in some daughter cells. Some genetic loci, which are active in naive cells, however, become silenced during terminal differentiation. Both the derepression of silent loci and the silencing of active loci appear to be linked to the process of DNA replication. Future investigation will be directed toward understanding the way in which patterns of gene expression are altered or transmitted during the cell division of helper T lymphocytes.

Animals↗