Susan Kovats

Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States

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Publications (40)261.01 Total impact

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    ABSTRACT: Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC (cDC) subsets, CD11b(-) (cDC1s) or CD11b(+) (cDC2s), arise via distinct networks of transcription factors involving IFN regulatory factor 4 (IRF4) and IRF8, and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c(+) cells, we determined whether IRF4 or IRF8 deficiency beginning in CD11c(+) cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis, and spleen. CD11c-cre-Irf4(-/-) mice selectively lacked a lung-resident CD11c(hi)CD11b(+)SIRPα(+)CD24(+) DC subset, but not other lung CD11b(+) DCs or alveolar macrophages. Numbers of CD11b(+)CD4(+) splenic DCs, but not CD11b(+) dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8(-/-) mice lacked lung-resident CD103(+) DCs and splenic CD8α(+) DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8(-/-) pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that, although one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and, therefore, regulate the magnitude of DC functional responses.
    No preview · Article · Jan 2016 · The Journal of Immunology
  • Susan Kovats
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    ABSTRACT: Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ER) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells.
    No preview · Article · Feb 2015 · Cellular Immunology
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    Esther Carreras · Susan Kovats
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    ABSTRACT: Although some hematopoietic cell types are known to respond to sex hormones, hematopoietic stem cells (HSCs) are generally thought to function similarly in both sexes. Recently in Nature, Nakada et al. (2014) show that HSCs respond to higher levels of estrogen in females, resulting in enhanced self-renewal and increased erythropoiesis.
    Preview · Article · Feb 2014 · Cell stem cell
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    ABSTRACT: E protein transcription factors and their natural inhibitors, Id proteins, play critical and complex roles during lymphoid development. In this article, we report that partial maintenance of E protein activity during positive selection results in a change in the cell fate determination of developing iNKT cells, with a block in the development of iNKT1 cells and a parallel increase in the iNKT2 and iNKT17 subsets. Because the expression levels of the transcription factors that drive these alternative functional fates (GATA-3, RORγT, T-bet, and Runx-3) are not altered, our results suggest that E protein activity controls a novel checkpoint that regulates the number of iNKT precursors that choose each fate.
    No preview · Article · Oct 2013 · The Journal of Immunology
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    ABSTRACT: Migration of resident dendritic cells (DC) from the skin to local lymph nodes (LN) triggers T cell-mediated immune responses during cutaneous infection, autoimmune disease, and vaccination. In this study, we investigated whether the development and migration of skin-resident DC were regulated by IFN regulatory factor 4 (IRF4), a transcription factor that is required for the development of CD11b(+) splenic DC. We found that the skin of naive IRF4(-/-) mice contained normal numbers of epidermal Langerhans cells (eLC) and increased numbers of CD11b(+) and CD103(+) dermal DC (dDC) populations, indicating that tissue DC development and skin residency is not disrupted by IRF4 deficiency. In contrast, numbers of migratory eLC and CD11b(+) dDC were significantly reduced in the cutaneous LN of IRF4(-/-) mice, suggesting a defect in constitutive migration from the dermis during homeostasis. Upon induction of skin inflammation, CD11b(+) dDC in IRF4(-/-) mice did not express the chemokine receptor CCR7 and failed to migrate to cutaneous LN, whereas the migration of eLC was only mildly impaired. Thus, although dispensable for their development, IRF4 is crucial for the CCR7-mediated migration of CD11b(+) dDC, a predominant population in murine and human skin that plays a vital role in normal and pathogenic cutaneous immunity.
    Full-text · Article · Aug 2012 · The Journal of Immunology
  • Susan Kovats
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    ABSTRACT: This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Immune cells and hematopoietic progenitors express estrogen receptors (ER). As ligand-activated transcription factors that modulate chromatin structure, ER regulate transcriptional programs that direct the development or functional responses of immune cells. ER-regulated immune responses likely contribute to significant sex biases in infection, autoimmunity and other inflammatory diseases, and changes in immune function during the female hormonal cycle and pregnancy. Here we summarize our own and others' studies showing that ERα signaling regulates the development of dendritic cells (DCs), antigen-presenting cells crucial for initiation of innate and adaptive immunity. During inflammation, elevated GM-CSF directs the development of new DCs from monocytes or other precursors that infiltrate tissues and lymphoid organs, and these de novo populations of inflammatory DCs have critical roles in programming T cell-mediated responses during infection and autoimmunity. Estradiol acting via ERα, but not ERβ, promotes the GM-CSF-mediated inflammatory pathway of DC differentiation, leading to the development of DCs with increased functional capacity. Estradiol/ERα signaling acts directly in GM-CSF-stimulated myeloid progenitors to induce elevated levels of IRF4, a transcription factor that directs a developmental program underlying CD11b(+) DC differentiation. In contrast, during homeostatic Flt3 Ligand-driven DC development, ERα signaling decreases numbers of myeloid progenitors and differentiated DCs, yet promotes more functionally competent DCs. Thus ERα signaling regulates the response of DC progenitors to the external cytokine environment, thereby altering the strength or integrity of DC developmental pathways. The development of increased numbers of DCs during inflammation will likely increase the magnitude of DC-mediated functional responses including cytokine production, processing and MHC-mediated presentation of antigens, and activation and polarization of T and B lymphocytes; these functions also may be regulated directly by ERα signaling. In sum, via profound effects on DC development and ensuing functional responses, ERα signaling can regulate the quality of the adaptive immune responses and influence the resolution of infection or chronic inflammatory diseases.
    No preview · Article · Apr 2012 · Hormones and Behavior
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    ABSTRACT: CD1d-restricted type I NKT cells provide help for specific antibody production. B cells, which have captured and presented a T-dependent, antigen-derived peptide on MHC class II and CD1d-binding glycolipid α-GC on CD1d, respectively, activate Th and NKT cells to elicit B cell help. However, the role of the DC CD1d in humoral immunity remains unknown. We therefore constructed mixed bone marrow chimeras containing CD1d-expressing, DTR-transgenic DCs and CD1d(+) or CD1d(-) nontransgenic DCs. Following DT-mediated DC ablation and immunization, we observed that the primary and secondary antibody responses were equivalent in the presence of CD1d(+) and CD1d(-) DCs. In contrast, a total ablation of DCs delayed the primary antibody response. Further experiments revealed that depletion of CD1d(+) DCs blocked in vivo expansion of antigen-specific cytotoxic (CD8(+)) T lymphocytes. These results provide a clear demonstration that although CD1d expression on DCs is essential for NKT-enhanced CD8(+) T cell expansion, it is dispensable for specific antibody production.
    No preview · Article · Feb 2012 · Journal of leukocyte biology

  • No preview · Conference Paper · May 2011
  • Susan Kovats · Esther Carreras · Hemant Agrawal
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    ABSTRACT: Lymphocytes and myeloid cells express estrogen, progesterone, and androgen receptors, and studies show that sex steroid hormones directly modulate their activation, lifespan, and functional response during innate and adaptive immunity. Hematopoietic progenitors also express estrogen and androgen receptors, and profound effects of sex hormones on development of lymphoid and myeloid cells have been reported. The sex steroid receptors act as nuclear transcription factors, via multiple ligand-dependent or ligand-independent mechanisms. Sex steroid receptors also mediate rapid signaling events that synergize with membrane receptor signaling. The basis of sex-based differences in immunity will be clarified by determination of the potentially diverse molecular mechanisms by which sex steroid receptor signaling regulates immune cell development and function.
    No preview · Chapter · Jan 2010
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    ABSTRACT: The signal transduction events supporting B cell antigen receptor (BCR) endocytosis are not well understood. We have identified a pathway supporting BCR internalization that begins with tyrosine phosphorylation of the adapter protein LAB. Phosphorylated LAB recruits a complex of Grb2-dynamin and the guanine nucleotide exchange factor Vav. Vav is required for activation of the small GTPases Rac1 and Rac2. All these proteins contribute to (and dynamin, Vav, and Rac1/2 are required for) BCR endocytosis and presentation of antigen to T cells. This is the first description of a sequential signal transduction pathway from BCR to internalization and antigen presentation.
    Preview · Article · Oct 2009 · Journal of Biological Chemistry
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    ABSTRACT: During inflammation, elevated granulocyte macrophage-colony-stimulating factor (GM-CSF) directs the development of new dendritic cells (DCs). This pathway is influenced by environmental factors, and we previously showed that physiologic levels of estradiol, acting through estrogen receptor alpha (ERalpha), promote the GM-CSF-mediated differentiation of a CD11b(+) DC subset from myeloid progenitors (MPs). We now have identified interferon regulatory factor 4 (IRF4), a transcription factor induced by GM-CSF and critical for CD11b(+) DC development in vivo, as a target of ERalpha signaling during this process. In MPs, ERalpha potentiates and sustains GM-CSF induction of IRF4. Furthermore, retroviral delivery of the Irf4 cDNA to undifferentiated ERalpha(-/-) bone marrow cells restored the development of the estradiol/ERalpha-dependent DC population, indicating that an elevated amount of IRF4 protein substitutes for ERalpha signaling. Thus at an early stage in the MP response to GM-CSF, ERalpha signaling induces an elevated amount of IRF4, which leads to a developmental program underlying CD11b(+) DC differentiation.
    Full-text · Article · Oct 2009 · Blood
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    ABSTRACT: Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR(-/-) mice. Numbers of activated CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR(-/-) spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR(-/-) DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR(-/-) DC produced less IL-12p40/70 and TNF-alpha than did NZM DC. The limited IFNAR(-/-) DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4(+) T cells and CD19(+) B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.
    Full-text · Article · Oct 2009 · The Journal of Immunology
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    ABSTRACT: Antigen binding to the B cell antigen receptor (BCR) initiates an array of signaling events. These include endocytosis of ligand-receptor complexes via clathrin-coated pits, trafficking of the internalized ligand to lysosomes, degradation of the associated proteins to peptides, and peptide presentation on nascent major histocompatibility complex class II to T cells. The signal transduction events supporting BCR internalization are not well understood. We have identified a pathway supporting BCR internalization that includes the Vav1 and/or Vav3 isoforms and the GTPase dynamin. Vav1 and -3 are not required for B cell development and maturation, nor for a variety of BCR-induced signaling events nor for BCR signaling leading to major histocompatibility complex class II and CD80 expression, but Vav1 and/or -3 are absolutely required for BCR endocytosis and BCR-induced Rac-GTP loading. This is the first demonstration of a link between Vav and Rac in BCR internalization leading to antigen presentation to T cells.
    No preview · Article · Aug 2009 · Journal of Biological Chemistry
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    Amr H Sawalha · Susan Kovats
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    ABSTRACT: Dehydroepiandrosterone (DHEA) is a weak androgen that exerts pleomorphic effects on the immune system. The hormone has no known receptor, and consequently, its mechanism of action on immunocompetent cells remains poorly understood. Interestingly, serum levels of DHEA are decreased in patients with inflammatory diseases including lupus, and these levels seem to correlate inversely with disease activity. Following encouraging studies demonstrating beneficial effects of DHEA supplementation in murine lupus models, several clinical studies have tested the effect of DHEA in lupus patients. DHEA treatment could improve overall quality-of-life assessment measures and glucocorticoid requirements in some lupus patients with mild to moderate disease; however, DHEA's effect on disease activity in lupus patients remains controversial. Long-term safety studies are required in light of the reported effect of DHEA supplementation in lowering high-density lipoprotein cholesterol in lupus patients.
    Preview · Article · Sep 2008 · Current Rheumatology Reports
  • Susan Kovats
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    ABSTRACT: Gorilla Mountain. The Story of Wildlife Biologist Amy Vedder. Rene Ebersole. Franklin Watts (Scholastic), New York, and Joseph Henry (National Academies Press), Washington, DC, 2005. 128 pp. $9.95. ISBN 9780309095518. Robo World. The Story of Robot Designer Cynthia Breazeal. Jordan D. Brown. Franklin Watts (Scholastic), New York, and Joseph Henry (National Academies Press), Washington, DC, 2005. 128 pp. $9.95. ISBN 9780309095563. Nature's Machines. The Story of Biomechanist Mimi Koehl. Deborah Parks. Franklin Watts (Scholastic), New York, and Joseph Henry (National Academies Press), Washington, DC, 2005. 128 pp. $9.95. ISBN 9780309095594. Three books from the Women's Adventures in Science series present the experiences and research of a wildlife biologist, a robot designer, and a biomechanist to encourage young readers' interests.
    No preview · Article · Jul 2008 · Science
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    Susan Kovats · Esther Carreras
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    ABSTRACT: Estrogen receptor (ER) ligands can modulate innate and adaptive immunity and hematopoiesis, which may explain the clear sex differences in immune responses during autoimmunity, infection or trauma. Dendritic cells (DC) are antigen presenting cells important for initiation of innate and adaptive immunity, as well as immune tolerance. DC progenitors and terminally differentiated DC express ER, indicating the ER ligands may regulate DC at multiple developmental and functional stages. Although there are profound differences in innate immunity between males and females or upon systemic imposition of sex hormones, studies are just beginning to link these differences to DC. Our and others studies demonstrate that estradiol and other ER ligands regulate the homeostasis of bone marrow myeloid and lymphoid progenitors of DC, as well as DC differentiation mediated by GM-CSF and Flt3 Ligand. Since DC have a brief lifespan, these data suggest that relatively short exposures to ER ligands in vivo will alter DC numbers and intrinsic functional capacity related to their developmental state. Studies in diverse experimental models also show that agonist and antagonist ER ligands modulate DC activation and production of inflammatory mediators. These findings have implications for human health and disease since they suggest that both DC development and functional capacity will be responsive to the physiological, pharmacological and environmental ER ligands to which an individual is exposed in vivo.
    Preview · Article · Mar 2008 · Cellular Immunology
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    ABSTRACT: Estrogen receptor (ER) ligands modulate hemopoiesis and immunity in the normal state, during autoimmunity, and after infection or trauma. Dendritic cells (DC) are critical for initiation of innate and adaptive immune responses. We demonstrate, using cytokine-driven culture models of DC differentiation, that 17-beta-estradiol exerts opposing effects on differentiation mediated by GM-CSF and Flt3 ligand, the two cytokines that regulate DC differentiation in vivo. We also show that estradiol acts on the same highly purified Flt3+ myeloid progenitors (MP) to differentially regulate the DC differentiation in each model. In GM-CSF-supplemented cultures initiated from MP, physiological amounts of estradiol promoted differentiation of Langerhans-like DC. Conversely, in Flt3 ligand-supplemented cultures initiated from the same MP, estradiol inhibited cell survival in a dose-dependent manner, thereby decreasing the yield of plasmacytoid and conventional myeloid and lymphoid DC. Experiments with bone marrow cells from ER-deficient mice and the ER antagonist ICI182,780 showed that estradiol acted primarily via ERalpha to regulate DC differentiation. Thus, depending on the cytokine environment, pathways of ER signaling and cytokine receptor signaling can differentially interact in the same Flt3+ MP to regulate DC development. Because the Flt3 ligand-mediated differentiation pathway is important during homeostasis, and GM-CSF-mediated pathways are increased by inflammation, our data suggest that endogenous or pharmacological ER ligands may differentially affect DC development during homeostasis and disease, with consequent effects on DC-mediated immunity.
    Full-text · Article · Feb 2008 · The Journal of Immunology

  • No preview · Article · Dec 2007 · Clinical Immunology
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    ABSTRACT: Several MHC class II alleles linked with autoimmune diseases form unusually low stability complexes with CLIP, leading us to hypothesize that this is an important feature contributing to autoimmune pathogenesis. To investigate cellular consequences of altering class II/CLIP affinity, we evaluated invariant chain (Ii) mutants with varying CLIP affinity for a mouse class II allele, I-E(d), which has low affinity for wild-type CLIP and is associated with a mouse model of spontaneous, autoimmune joint inflammation. Increasing CLIP affinity for I-E(d) resulted in increased cell surface and total cellular abundance and half-life of I-E(d). This reveals a post-endoplasmic reticulum chaperoning capacity of Ii via its CLIP peptides. Quantitative effects on I-E(d) were less pronounced in DM-expressing cells, suggesting complementary chaperoning effects mediated by Ii and DM, and implying that the impact of allelic variation in CLIP affinity on immune responses will be highest in cells with limited DM activity. Differences in the ability of cell lines expressing wild-type or high-CLIP-affinity mutant Ii to present Ag to T cells suggest a model in which increased CLIP affinity for class II serves to restrict peptide loading to DM-containing compartments, ensuring proper editing of antigenic peptides.
    Full-text · Article · Dec 2007 · The Journal of Immunology
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    ABSTRACT: To assess the ability of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) to function as antigen-presenting cells (APCs) for arthritogenic autoantigens found within inflamed joint tissues. Human class II major histocompatibility complex (MHC)-typed FLS were used as APCs for murine class II MHC-restricted CD4 T cell hybridomas. Interferon-gamma (IFNgamma)-treated, antigen-loaded FLS were cocultured with T cell hybridomas specific for immunodominant portions of human cartilage gp-39 (HC gp-39) or human type II collagen (CII). T cell hybridoma activation was measured by enzyme-linked immunosorbent assay of culture supernatants for interleukin-2. Both synthetic peptide and synovial fluid (SF) were used as sources of antigen. APC function in cocultures was inhibited by using blocking antibodies to human class II MHC, CD54, or CD58, or to murine CD4, CD11a, or CD2. Human FLS could present peptides from the autoantigens HC gp-39 and human CII to antigen-specific MHC-restricted T cell hybridomas. This response required pretreatment of FLS with IFNgamma, showed MHC restriction, and was dependent on human class II MHC and murine CD4 for effective antigen presentation. Furthermore, FLS were able to extract and present antigens found within human SF to both the HC gp-39 and human CII T cell hybridomas in an IFNgamma-dependent and MHC-restricted manner. RA FLS can function as APCs and are able to present peptides derived from autoantigens found within joint tissues to activated T cells in vitro. In the context of inflamed synovial tissues, FLS may be an important and hitherto overlooked subset of APCs that could contribute to autoreactive immune responses.
    Full-text · Article · May 2007 · Arthritis & Rheumatology

Publication Stats

2k Citations
261.01 Total Impact Points

Institutions

  • 2007-2015
    • Oklahoma Medical Research Foundation
      • Arthritis and Clinical Immunology Program
      Oklahoma City, Oklahoma, United States
    • Stanford University
      Stanford, California, United States
  • 2003-2007
    • Beckman Research Institute
      Duarte, California, United States
  • 2005
    • City of Hope National Medical Center
      • Department of Immunology
      Duarte, California, United States
  • 1995-2001
    • University of Washington Seattle
      • Department of Immunology
      Seattle, WA, United States
  • 1998
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1993-1997
    • Virginia Mason Medical Center
      Seattle, Washington, United States