Barbara L Kee

University of Chicago, Chicago, Illinois, United States

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Publications (62)695.14 Total impact

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    ABSTRACT: Microbiota-mediated effects on the host immune response facilitate colonization resistance against pathogens. However, it is unclear whether and how the host immune response can regulate the microbiota to mediate colonization resistance. ID2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice in which ID2 is deleted from differentiated ILC3s, we observed that these mutant mice exhibited greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we showed that the ID2-dependent early colonization resistance was mediated by interleukin-22 (IL-22) regulation of the microbiota. In addition to regulating development, ID2 maintained homeostasis of ILC3s and controlled IL-22 production through an aryl hydrocarbon receptor (AhR) and IL-23 receptor pathway. Thus, ILC3s can mediate immune surveillance, which constantly maintains a proper microbiota, to facilitate early colonization resistance through an ID2-dependent regulation of IL-22. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 04/2015; 42(4):731-43. DOI:10.1016/j.immuni.2015.03.012 · 19.75 Impact Factor
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    ABSTRACT: Invariant natural killer T cells (iNKT cells) are innate-like T cells that rapidly produce cytokines that impact antimicrobial immune responses, asthma, and autoimmunity. These cells acquire multiple effector fates during their thymic development that parallel those of CD4(+) T helper cells. The number of Th2-type effector iNKT cells is variable in different strains of mice, and their number impacts CD8 T, dendritic, and B cell function. Here we demonstrate a unique function for the transcription factor lymphoid enhancer factor 1 (LEF1) in the postselection expansion of iNKT cells through a direct induction of the CD127 component of the receptor for interleukin-7 (IL-7) and the transcription factor c-myc. LEF1 also directly augments expression of the effector fate-specifying transcription factor GATA3, thus promoting the development of Th2-like effector iNKT cells that produce IL-4, including those that also produce interferon-γ. Our data reveal LEF1 as a central regulator of iNKT cell number and Th2-type effector differentiation. © 2015 Carr et al.
    Journal of Experimental Medicine 04/2015; DOI:10.1084/jem.20141849 · 13.91 Impact Factor
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    ABSTRACT: Innate lymphoid cells (ILCs) are a family of effectors that originate from a common innate lymphoid cell progenitor. However, the transcriptional program that sets the identity of the ILC lineage remains elusive. Here, we show that NFIL3 is a critical regulator of the common helper-like innate lymphoid cell progenitor (CHILP). Cell-intrinsic Nfil3 ablation led to variably impaired development of fetal and adult ILC subsets. Conditional gene targeting demonstrated that NFIL3 exerted its function prior to ILC subset commitment. Accordingly, NFIL3 ablation resulted in loss of ID2(+) CHILP and PLZF(+) ILC progenitors. Nfil3 expression in lymphoid progenitors was under the control of the mesenchyme-derived hematopoietin IL-7, and NFIL3 exerted its function via direct Id2 regulation in the CHILP. Moreover, ectopic Id2 expression in Nfil3-null precursors rescued defective ILC lineage development in vivo. Our data establish NFIL3 as a key regulator of common helper-like ILC progenitors as they emerge during early lymphopoiesis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(12). DOI:10.1016/j.celrep.2015.02.057 · 7.21 Impact Factor
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    ABSTRACT: The chemokine receptor CCR9 controls the immigration of multipotent hematopoietic progenitor cells into the thymus to sustain T cell development. Postimmigration, thymocytes downregulate CCR9 and migrate toward the subcapsular zone where they recombine their TCR β-chain and γ-chain gene loci. CCR9 is subsequently upregulated and participates in the localization of thymocytes during their selection for self-tolerant receptor specificities. Although the dynamic regulation of CCR9 is essential for early T cell development, the mechanisms controlling CCR9 expression have not been determined. In this article, we show that key regulators of T cell development, Notch1 and the E protein transcription factors E2A and HEB, coordinately control the expression of Ccr9. E2A and HEB bind at two putative enhancers upstream of Ccr9 and positively regulate CCR9 expression at multiple stages of T cell development. In contrast, the canonical Notch signaling pathway prevents the recruitment of p300 to the putative Ccr9 enhancers, resulting in decreased acetylation of histone H3 and a failure to recruit RNA polymerase II to the Ccr9 promoter. Although Notch signaling modestly modulates the binding of E proteins to one of the two Ccr9 enhancers, we found that Notch signaling represses Ccr9 in T cell lymphoma lines in which Ccr9 transcription is independent of E protein function. Our data support the hypothesis that activation of Notch1 has a dominant-negative effect on Ccr9 transcription and that Notch1 and E proteins control the dynamic expression of Ccr9 during T cell development. Copyright © 2015 by The American Association of Immunologists, Inc.
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    ABSTRACT: The immune system can be divided into innate and adaptive components that differ in their rate and mode of cellular activation, with innate immune cells being the first responders to invading pathogens. Recent advances in the identification and characterization of innate lymphoid cells have revealed reiterative developmental programs that result in cells with effector fates that parallel those of adaptive lymphoid cells and are tailored to effectively eliminate a broad spectrum of pathogenic challenges. However, activation of these cells can also be associated with pathologies such as autoimmune disease. One major distinction between innate and adaptive immune system cells is the constitutive expression of ID proteins in the former and inducible expression in the latter. ID proteins function as antagonists of the E protein transcription factors that play critical roles in lymphoid specification as well as B- and T-lymphocyte development. In this review, we examine the transcriptional mechanisms controlling the development of innate lymphocytes, including natural killer cells and the recently identified innate lymphoid cells (ILC1, ILC2, and ILC3), and innate-like lymphocytes, including natural killer T cells, with an emphasis on the known requirements for the ID proteins.
    Immunological Reviews 09/2014; 261(1). DOI:10.1111/imr.12203 · 12.91 Impact Factor
  • Barbara L Kee
    Blood 06/2014; 123(26):4009-10. DOI:10.1182/blood-2014-05-574178 · 9.78 Impact Factor
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    ABSTRACT: Invariant NKT (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. In this study, we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the postselection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development.
    The Journal of Immunology 11/2013; 191(12). DOI:10.4049/jimmunol.1301521 · 5.36 Impact Factor
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    Fotini Gounari, Barbara L Kee
    Nature Immunology 10/2013; 14(10):1034-5. DOI:10.1038/ni.2709 · 24.97 Impact Factor
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    ABSTRACT: The E2A transcription factors promote the development of thymus-seeding cells but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. Here we showed that E2A proteins were required to promote T lymphocyte commitment from DN2 thymocytes and to extinguish their potential for alternative fates. E2A proteins functioned in DN2 cells to limit expression of Gata3, which encodes an essential T lymphocyte transcription factor whose ectopic expression can arrest T cell differentiation. Genetic, or siRNA-mediated, reduction of Gata3 rescued T cell differentiation in the absence of E2A and restricted the development of alternative lineages by limiting the expanded self-renewal potential in E2A(-/-) DN2 cells. Our data support a novel paradigm in lymphocyte lineage commitment in which the E2A proteins are necessary to limit the expression of an essential lineage specification and commitment factor in order to restrain self-renewal and prevent an arrest in differentiation.
    Blood 01/2013; 121(9). DOI:10.1182/blood-2012-08-449447 · 9.78 Impact Factor
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    ABSTRACT: Lineage commitment is regulated during hematopoiesis, with stepwise loss of differentiation potential ultimately resulting in lineage commitment. In this study we describe a novel population of B/NK bipotent precursors among common lymphoid progenitors in the fetal liver and the bone marrow. The absence of T cell precursor potential, both in vivo and in vitro, is due to low Notch1 expression and secondary to inhibition of E2A activity by members of the inhibitor of DNA binding (Id) protein family. Our results demonstrate a new, Id protein-dependent, molecular mechanism of Notch1 repression, operative in both fetal and adult common lymphoid progenitors, where T cell potential is selectively inhibited without affecting either the B or NK programs. This study identifies Id proteins as negative regulators of T cell specification, before B and NK commitment, and provides important insights into the transcriptional networks orchestrating hematopoiesis.
    The Journal of Immunology 09/2012; 189(8):3822-30. DOI:10.4049/jimmunol.1103723 · 5.36 Impact Factor
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    ABSTRACT: Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1(-/-) NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.
    Immunity 05/2012; 36(6):921-32. DOI:10.1016/j.immuni.2012.04.006 · 19.75 Impact Factor
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    ABSTRACT: During B lymphopoiesis, recombination of the locus encoding the immunoglobulin κ-chain complex (Igk) requires expression of the precursor to the B cell antigen receptor (pre-BCR) and escape from signaling via the interleukin 7 receptor (IL-7R). By activating the transcription factor STAT5, IL-7R signaling maintains proliferation and represses Igk germline transcription by unknown mechanisms. We demonstrate that a STAT5 tetramer bound the Igk intronic enhancer (E(κi)), which led to recruitment of the histone methyltransferase Ezh2. Ezh2 marked trimethylation of histone H3 at Lys27 (H3K27me3) throughout the κ-chain joining region (J(κ)) to the κ-chain constant region (C(κ)). In the absence of Ezh2, IL-7 failed to repress Igk germline transcription. H3K27me3 modifications were lost after termination of IL-7R-STAT5 signaling, and the transcription factor E2A bound E(κi), which resulted in acquisition of H3K4me1 and acetylated histone H4 (H4Ac). Genome-wide analyses showed a STAT5 tetrameric binding motif associated with transcriptional repression. Our data demonstrate how IL-7R signaling represses Igk germline transcription and provide a general model for STAT5-mediated epigenetic transcriptional repression.
    Nature Immunology 12/2011; 12(12):1212-20. DOI:10.1038/ni.2136 · 24.97 Impact Factor
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    Barbara L Kee
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    ABSTRACT: Recently in Cell, Novershtern et al. (2011) reported a comprehensive transcriptome analysis of human hematopoiesis, combined with sophisticated bioinformatics analysis and high-throughput DNA binding data for multiple transcription factors. The resulting map of regulatory interactions controlling stem cell differentiation provides a valuable resource for identification of novel hematopoietic regulators.
    Cell stem cell 02/2011; 8(2):122-4. DOI:10.1016/j.stem.2011.01.006 · 22.15 Impact Factor
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    ABSTRACT: Loss of the transcription factor Ikaros is correlated with Notch receptor activation in T cell acute lymphoblastic leukemia (T-ALL). However, the mechanism remains unknown. We identified promoters in Notch1 that drove the expression of Notch1 proteins in the absence of a ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5'-alternative promoters initiated a feedback loop, augmenting Notch1 signaling. Ikaros also repressed intragenic promoters for ligand-independent Notch1 proteins that are cryptic in wild-type cells, poised in preleukemic cells, and active in leukemic cells. Only ligand-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.
    Immunity 11/2010; 33(5):685-98. DOI:10.1016/j.immuni.2010.11.008 · 19.75 Impact Factor
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    Renée F de Pooter, Barbara L Kee
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    ABSTRACT: Lymphopoiesis generates mature B, T, and NK lymphocytes from hematopoietic stem cells via a series of increasingly restricted developmental intermediates. The transcriptional networks that regulate these fate choices are composed of both common and lineage-specific components, which combine to create a cellular context that informs the developmental response to external signals. E proteins are an important factor during lymphopoiesis, and E2A in particular is required for normal T- and B-cell development. Although the other E proteins, HEB and E2-2, are expressed during lymphopoiesis and can compensate for some of E2A's activity, E2A proteins have non-redundant functions during early T-cell development and at multiple checkpoints throughout B lymphopoiesis. More recently, a role for E2A has been demonstrated in the generation of lymphoid-primed multipotent progenitors and shown to favor their specification toward lymphoid over myeloid lineages. This review summarizes both our current understanding of the wide-ranging functions of E proteins during the development of adaptive lymphocytes and the novel functions of E2A in orchestrating a lymphoid-biased cellular context in early multipotent progenitors.
    Immunological Reviews 11/2010; 238(1):93-109. DOI:10.1111/j.1600-065X.2010.00957.x · 12.91 Impact Factor
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    ABSTRACT: Hemokinin-1, encoded by the TAC4 gene, is a tachykinin most closely related to substance P. Previous studies have shown that TAC4 distinguishes itself from other tachykinins by its predominantly non-neuronal expression profile, particularly in cells of the immune system. Here we report for the first time that the highest levels of TAC4 expression are found in the olfactory epithelium. Furthermore, we identify olfactory neuron-specific transcription factor (Olf-1), also known as early B-cell factor (EBF), as a novel regulator of TAC4 expression. EBF present in the olfactory epithelium and in B cells binds to two sites in the TAC4 promoter and modulates expression in developing B cells. Our findings suggest a role for TAC4 in cell differentiation, and represent a regulatory bridge between the nervous system and the immune system.
    Journal of neuroimmunology 10/2010; 232(1-2):41-50. DOI:10.1016/j.jneuroim.2010.09.027 · 2.79 Impact Factor
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    ABSTRACT: The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
    Nature medicine 10/2010; 16(11):1321-7. DOI:10.1038/nm.2246 · 28.05 Impact Factor
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    ABSTRACT: CD8(+) T cells are selected via low-affinity interaction with MHC class I molecules on thymic epithelial cells (TECs). However, compromised T cell receptor signaling was proposed to force CD8(+) T cell selection on hematopoietic cells through a SLAM-associated protein (SAP)-dependent mechanism similar to NKT cells. The outcome is an unconventional CD8(+) T cell with phenotypic and functional characteristics of innate lymphocytes. Here we showed that Id3(-/-) CD8(+) T cells had an innate-like phenotype and required SAP for their development. However, like conventional CD8(+) T cells, Id3(-/-) CD8(+) thymocytes were selected on TECs. The requirement for SAP and the innate-like phenotype was not intrinsic to Id3(-/-) CD8(+) thymocytes. Rather, an expanded population of NKT-like cells induced the innate phenotype on CD8(+) T cells through production of interleukin-4. Our findings reveal that accumulation of NKT-like cells promotes conventional CD8(+) thymocytes to acquire innate lymphocyte characteristics.
    Immunity 08/2010; 33(2):203-15. DOI:10.1016/j.immuni.2010.07.013 · 19.75 Impact Factor
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    Kevin Ramirez, Barbara L Kee
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    ABSTRACT: Natural killer (NK) cells are a subset of lymphocytes that kill virus-infected or cancerous cells and influence adaptive immune responses via production of inflammatory cytokines. Unlike B and T lymphocytes, no transcription factors have been identified that are essential for the emergence of NK cell progenitors from their multipotent precursors. We argue that this dearth of essential factors is because of the expression of redundant transcription factors that function at the earliest stages of development. However, multiple essential transcription factors have been identified at later stages of development. Recent studies have revealed novel subsets of NK cells with differing potential for target cell lysis and cytokine production. How these subsets arise from the conventional pathway of NK cell development and identification of the transcriptional networks that control their development are major challenges for future studies.
    Current opinion in immunology 03/2010; 22(2):193-8. DOI:10.1016/j.coi.2010.02.002 · 7.87 Impact Factor

Publication Stats

2k Citations
695.14 Total Impact Points

Institutions

  • 2002–2015
    • University of Chicago
      • • Department of Pathology
      • • Committee on Cancer Biology
      • • Committee on Immunology
      Chicago, Illinois, United States
    • Icahn School of Medicine at Mount Sinai
      Borough of Manhattan, New York, United States
  • 2007
    • The Walter and Eliza Hall Institute of Medical Research
      Melbourne, Victoria, Australia
  • 1998–2000
    • University of California, San Diego
      • Division of Biological Sciences
      San Diego, California, United States
  • 1992–1996
    • University of Toronto
      • Department of Immunology
      Toronto, Ontario, Canada
  • 1991
    • SickKids
      Toronto, Ontario, Canada