Publications (15)132.55 Total impact
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Article: IL-13-producing Th1 and Th17 cells characterize adaptive responses to both self and foreign antigens.
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ABSTRACT: In helper T cells, IL-13 is traditionally considered a Th2-type cytokine that is coexpressed with IL-4. Using mouse models of immunization and autoimmunity, we demonstrate that IL-13 is frequently uncoupled from IL-4, and that it can be produced by both IFN-γ(+) Th1 cells and IL-17(+) Th17 cells. We report that these IL-13-producing Th1 and Th17 cells are distinct from classical IL-4(+) Th2 cells and that they are relatively common, appearing in the context of both protective and pathogenic T-cell responses. We also demonstrate that IL-13 and Th2-type cytokines can have important consequences in Th1- and Th17-dominated settings, such as lymphopenia-induced autoimmune disease, where they can be either pro- or anti-inflammatory, depending on whether they act on innate or adaptive immune cells. Taken together, our studies indicate that IL-13 production is more widespread than previously appreciated and that blocking this cytokine may have therapeutic benefits even in settings where traditional IL-4-driven Th2-type responses are not evident.European Journal of Immunology 06/2012; 42(9):2322-8. · 5.10 Impact Factor -
Article: Posttranscriptional silencing of effector cytokine mRNA underlies the anergic phenotype of self-reactive T cells.
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ABSTRACT: Self-reactive T cell clones that escape negative selection are either deleted or rendered functionally unresponsive (anergic), thus preventing them from propagating host tissue damage. By using an in vivo model, we investigated molecular mechanisms for T cell tolerance, finding that despite a characteristic inability to generate effector cytokine proteins, self-reactive T cells express large amounts of cytokine mRNAs. This disconnect between cytokine message and protein was not observed in T cells mounting productive responses to foreign antigens but, instead, was seen only in those responding to self, where the block in protein translation was shown to involve conserved AU-rich elements within cytokine 3'UTRs. These studies reveal that translation of abundant cytokine mRNAs is limited in self-reactive T cells and, thus, identify posttranscriptional silencing of antigen-driven gene expression as a key mechanism underlying the anergic phenotype of self-reactive T cells.Immunity 01/2011; 34(1):50-60. · 21.64 Impact Factor -
Article: STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms.
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ABSTRACT: Given the association with autoimmune disease, there is great interest in defining cellular factors that limit overactive or misdirected Th17-type inflammation. Using in vivo and in vitro models, we investigated the molecular mechanisms for cytokine-mediated inhibition of Th17 responses, focusing on the role of STAT1 and T-bet in this process. These studies demonstrate that, during systemic inflammation, STAT1- and T-bet-deficient T cells each exhibit a hyper-Th17 phenotype relative to wild-type controls. However, IL-17 production was greater in the absence of T-bet, and when both STAT1 and T-bet were deleted, there was no further increase, with the double-deficient cells instead behaving more like STAT1-deficient counterparts. Similar trends were observed during in vitro priming, with production of Th17-type cytokines greater in T-bet(-/-) T cells than in either STAT1(-/-) or STAT1(-/-) T-bet(-/-) counterparts. The ability of IFN-γ and IL-27 to suppress Th17 responses was reduced in T-bet-deficient cells, and most importantly, ectopic T-bet could suppress signature Th17 gene products, including IL-17A, IL-17F, IL-22, and retinoic acid-related orphan receptor γT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-γ, IL-27, and likely all STAT1-activating cytokines, there are both STAT1 and T-bet-dependent pathways capable of suppressing Th17 responses.The Journal of Immunology 10/2010; 185(11):6461-71. · 5.79 Impact Factor -
Article: Duration of antigen receptor signaling determines T-cell tolerance or activation.
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ABSTRACT: The early events that determine the decision between lymphocyte tolerance and activation are not well-understood. Using a model of systemic self-antigen recognition by CD4(+) T cells, we show, using single-cell biochemical analyses, that tolerance is characterized by transient signaling events downstream of T-cell receptor engagement in the mammalian target of rapamycin (mTOR) and NF-κB pathways. Parallel studies done by live cell imaging show that the key difference between tolerance and activation is the duration of the T cell-antigen presenting cell (APC) interaction, as revealed by stable T-cell immobilization on antigen encounter. Brief T cell-APC interactions result in tolerance, and prolonged interactions are associated with activation and the development of effector cells. These studies show that the duration of T cell-APC interactions and magnitude of associated TCR-mediated signaling are key determinants of lymphocyte tolerance vs. activation.Proceedings of the National Academy of Sciences 10/2010; 107(42):18085-90. · 9.68 Impact Factor -
Article: Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells.
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ABSTRACT: The possibility that effector T cells can be converted into forkhead box P3(+) regulatory T cells (Tregs) has potential therapeutic implications. To analyze the relationship between Th1 effectors and Tregs, we have used a model of systemic autoimmunity in which both effector and Tregs arise from a single population specific for a transgene-encoded systemic protein. In vitro, the presence of IFN-gamma inhibits Treg generation during activation. Using IFN-gamma reporter mice, we demonstrate that IFN-gamma-producing cells tend not to develop into Tregs, and Th1 priming of T cells prior to cell transfer limits the number of forkhead box P3(+) T cells generated in vivo. Moreover, transfer of IFN-gamma(-/-) or STAT1(-/-) T cells resulted in an increase in the number of Tregs. These data support a role for Th1 effector molecules and transcription factors in the control of peripheral Treg generation and demonstrates the limited plasticity of Th1 populations.The Journal of Immunology 11/2009; 184(1):30-4. · 5.79 Impact Factor -
Article: IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD.
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ABSTRACT: Members of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis in mice. We report that, compared with IL-10-deficient animals, which succumb to chronic intestinal disease at 3-6 months of age, mice lacking both IL-10 and the IL-27R (IL-27R/WSX-1) exhibit delayed pathology and prolonged survival (>1 year). Moreover, unlike highly susceptible IL-10-deficient counterparts, they were able to clear infection with Trichuris muris, a colon-dwelling nematode. In both models of intestinal inflammation, improved clinical outcome was associated with reduced inflammation and profound attenuation of T(h)1 responses and, consistent with these in vivo findings, we confirmed that during in vitro differentiation, IL-27 directly promotes CD4(+) T cell IFN-gamma production through effects on Tbet, a key T(h)1 transcription factor. We also found that its ability to suppress T(h)2 responses, which was clearly evident in helminth-infected IL-10-/-IL-27R-/- mice, was largely Tbet independent. Taken together, these studies demonstrate that, in the absence of IL-10, IL-27 can promote T(h)1-type and suppress T(h)2-type intestinal inflammation but, ultimately, is not required for the development of inflammatory bowel disease.International Immunology 07/2008; 20(6):739-52. · 3.41 Impact Factor -
Article: Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals.
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ABSTRACT: Although required for many fundamental immune processes, ranging from self-tolerance to pathogen immunity, interleukin (IL)-2 production is transient, and the mechanisms underlying this brevity remain unclear. These studies reveal that helper T cell IL-2 production is limited by a classic negative feedback loop that functions autonomously or in collaboration with other common gamma chain (IL-4 and IL-7) and IL-6/IL-12 family cytokines (IL-12 and IL-27). Consistent with this model for cytokine-dependent regulation, they also demonstrate that the inhibitory effect can be mediated by several signal transducer and activator of transcription (STAT) family transcription factors, namely STAT5, STAT4, and STAT6. Collectively, these findings establish that IL-2 production is limited by a network of autocrine and paracrine signals that are readily available during acute inflammatory responses and, thus, provide a cellular and molecular basis for its transient pattern of expression.Journal of Experimental Medicine 02/2007; 204(1):65-71. · 13.85 Impact Factor -
Article: Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease.
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ABSTRACT: To explore the interactions between regulatory T cells and pathogenic effector cytokines, we have developed a model of a T cell-mediated systemic autoimmune disorder resembling graft-versus-host disease. The cytokine responsible for tissue inflammation in this disorder is interleukin (IL)-17, whereas interferon (IFN)-gamma produced by Th1 cells has a protective effect in this setting. Because of the interest in potential therapeutic approaches utilizing transfer of regulatory T cells and inhibition of the IL-2 pathway, we have explored the roles of these in the systemic disease. We demonstrate that the production of IL-17 and tissue infiltration by IL-17-producing cells occur and are even enhanced in the absence of IL-2. Regulatory T cells favor IL-17 production but prevent the disease when administered early in the course by suppressing expansion of T cells. Thus, the pathogenic or protective effects of cytokines and the therapeutic capacity of regulatory T cells are crucially dependent on the timing and the nature of the disease.Journal of Experimental Medicine 01/2007; 203(13):2785-91. · 13.85 Impact Factor -
Article: Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system.
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ABSTRACT: Studies have focused on the events that influence the development of interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize T(H)-17 cell effector responses. Here we show that IL-27 receptor-deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development T(H)-17 cells induced by IL-6 and transforming growth factor-beta, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of T(H)-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.Nature Immunology 10/2006; 7(9):937-45. · 26.01 Impact Factor -
Article: IL-27 limits IL-2 production during Th1 differentiation.
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ABSTRACT: Although the ability of IL-27 to promote T cell responses is well documented, the anti-inflammatory properties of this cytokine remain poorly understood. The current work demonstrates that during infection with Toxoplasma gondii, IL-27R-deficient mice generate aberrant IL-2 responses that are associated with the development of a lethal inflammatory disease. Because in vivo depletion of IL-2 prolongs the survival of infected IL-27R-/- mice, these data suggest that IL-27 curbs the development of immunopathology by limiting parasite-induced IL-2 production. Consistent with this hypothesis, IL-27R-/- CD4+ T cells produce more IL-2 than wild-type counterparts during in vitro differentiation, and when rIL-27 is introduced, it can suppress the expression of IL-2 mRNA and protein by the latter group. Additionally, these studies reveal that, like IL-27, IL-12 can inhibit IL-2 production, and although each employs distinct mechanisms, they can synergize to enhance the effect. In contrast, this property is not shared by closely related cytokines IL-6 and IL-23. Thus, while traditionally viewed as proinflammatory agents, the present findings establish that IL-27 and IL-12 cooperate to limit the availability of IL-2, a potent T cell growth and survival factor. Moreover, because the current studies demonstrate that both can induce expression of suppressor of cytokine signaling 3, a protein that tempers cytokine receptor signaling, they also suggest that IL-27 and IL-12 share additionally inhibitory properties.The Journal of Immunology 02/2006; 176(1):237-47. · 5.79 Impact Factor -
Article: Positive and negative regulation of the IL-27 receptor during lymphoid cell activation.
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ABSTRACT: Previous reports have focused on the ability of IL-27 to promote naive T cell responses but the present study reveals that surface expression of WSX-1, the ligand-specific component of the IL-27R, is low on these cells and that highest levels are found on effector and memory CD4(+) and CD8(+) T cells. Accordingly, during infection with Toxoplasma gondii, in vivo T cell activation is associated with enhanced expression of WSX-1, and, in vitro, TCR ligation can induce expression of WSX-1 regardless of the polarizing (Th1/Th2) environment present at the time of priming. However, while these data establish that mitogenic stimulation promotes expression of WSX-1 by T cells, activation of NK cells and NKT cells prompts a reduction in WSX-1 levels during acute toxoplasmosis. Together, with the finding that IL-2 can suppress expression of WSX-1 by activated CD4(+) T cells, these studies indicate that surface levels of the IL-27R can be regulated by positive and negative signals associated with lymphoid cell activation. Additionally, since high levels of WSX-1 are evident on resting NK cells, resting NKT cells, effector T cells, regulatory T cells, and memory T cells, the current work demonstrates that IL-27 can influence multiple effector cells of innate and adaptive immunity.The Journal of Immunology 07/2005; 174(12):7684-91. · 5.79 Impact Factor -
Article: TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development.
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ABSTRACT: During infection, CD4(+) Th cell responses polarize to become primarily Th1 or Th2. Th1 cells, which make IFN-gamma, are crucial for immunity to many bacterial and protozoal infections, whereas Th2 cells, which make IL-4, IL-5, and IL-13, are important for resistance to helminth infections. Polarized Th1 responses are induced by dendritic cells (DCs), which respond to pathogen-derived TLR ligands to produce IL-12 and related cytokines that are instrumental in Th1 cell outgrowth, and coordinately process and present Ag in the context of MHC class II to activate naive Th cells. In this study we show that in addition to providing positive signals for Th1 cell development, mouse DCs activated by TLR engagement can also provide a potent negative signal that prevents the development of Th2 cells. Production of this signal, which is not IL-12, IL-18, IL-23, IL-27, or IFN-gamma and is not provided via Th1 cells, is dependent upon a MyD88-dependent, TNF receptor-associated factor-6-independent signaling pathway in DCs. The signal is released from DCs in response to activation via TLR ligands and exerts an effect directly on Th cells rather than through a third-party cell. Our findings indicate that DCs can provide potent negative as well as positive instruction for Th response polarization, and that these instructional signals are distinct and independent.The Journal of Immunology 02/2005; 174(2):742-51. · 5.79 Impact Factor -
Article: Understanding the pro- and anti-inflammatory properties of IL-27.
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ABSTRACT: The recent identification of IL-27 (IL-27p28/EBV-induced gene 3) and IL-27R (WSX-1/gp130) has provided new insights for the biology of IL-6/IL-12 family cytokines. Initial studies indicated that IL-27 can directly regulate T cell functions and suggested an important role for it in promoting Th1 type responses. However, subsequent studies have revealed that IL-27R signaling influences a variety of immune cell types and can inhibit either Th1 or Th2 type responses. Though elucidation of the Jak/STAT signaling pathways activated by IL-27R ligation has unveiled some of the molecular mechanisms used by IL-27 to promote inflammation, little is known about the anti-inflammatory activities of this cytokine. Thus, the aim of this review is to discuss the pleotropic nature of the IL-27/IL-27R interaction and attempt to reconcile the pro- and anti-inflammatory properties of this immunomodulator.The Journal of Immunology 08/2004; 173(2):715-20. · 5.79 Impact Factor -
Article: Biology of recently discovered cytokines: discerning the pro- and anti-inflammatory properties of interleukin-27.
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ABSTRACT: IL-27 is a recently identified heterodimeric cytokine produced in response to microbial and host derived inflammatory cues. Initial studies indicated that IL-27 promotes the generation of Th1 responses required for resistance to intracellular infection and unveiled the molecular mechanisms mediating this effect. However, subsequent work uncovered a role for IL-27 in the suppression of Th1 and Th2 responses. Thus, by discussing its pleotropic functions in the context of infection-induced immunity and by drawing parallels to fellow IL-6/IL-12 family cytokines, this review will attempt to reconcile the pro- and anti-inflammatory effects of IL-27.Arthritis research & therapy 02/2004; 6(5):225-33. · 4.27 Impact Factor -
Article: Understanding the anti-inflammatory properties of interleukin-27 during infection and disease
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ABSTRACT: Upon microbial challenge, helper T cells orchestrate complex inflammatory responses that are specific for each invading pathogen and provide lasting immunity to re-infection. Though many factors can influence helper T cells, cytokines are critical in directing their differentiation into Th1 effector cells that promote resistance to intra-cellular pathogens or Th2 effector cells that combat helminths and extracellular pathogens. Additionally, since cytokines regulate the expansion and contraction of helper T cells, they ensure that immune responses are potent enough to protect the host and, at the same time, they protect from immune-mediated pathology once infection is resolved. IL-27 is a recently identified IL-6/IL-12 family cytokine whose receptor complex (IL-27R/GP130) is highly expressed by helper T cells. Initial studies reported that IL-27 can enhance T cell proliferation and that IL-27R is essential for efficient induction of Th1 responses. However, despite evidence that IL-27 is a pro-inflammatory factor, the work described in this dissertation reveals several anti-inflammatory properties for this cytokine. The following studies demonstrate that IL-27 is not required for the generation of appropriately polarized Th1 or Th2 responses during infection with T. gondii and T. muris , respectively. In these disease models, IL-27 does not determine the polarity of infection-induced inflammation Th1 vs. Th2) and, instead, delivers potent inhibitory cues that limit the intensity of helper T cell responses. Consistent with this hypothesis, the data presented here demonstrate that IL-27R is required to curb pathological T cell responses during infection with T. gondii , and they provide at least one cellular mechanism for this effect: IL-27 limits the production IL-2, a potent T cell growth and survival factor. Moreover, though it has been proposed that IL-27 acts primarily on naïve helper T cells and that a loss of IL-27R expression is concurrent to their differentiation into committed effector cells (Th1/Th2), the current studies demonstrate that naive T cell activation promotes expression of IL-27R and that receptor levels are highest on effector, regulatory and memory T cells. Given the viability of IL-27R-/- mice, these findings have identified IL-27 and IL-27R as novel targets for cytokine-based therapeutics meant to curb pathogenic inflammation.Dissertations available from ProQuest.
Top co-authors
Top Journals
Institutions
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2009–2012
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University of California, San Francisco
- Department of Pathology
San Francisco, CA, USA
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2006–2008
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Hospital of the University of Pennsylvania
Philadelphia, PA, USA
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2007
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CSU Mentor
Long Beach, CA, USA
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2004–2006
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University of Pennsylvania
- Department of Pathobiology
Philadelphia, PA, USA
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