Publications by authors named "Barbara L Kee"

59 Publications

The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude.

J Exp Med 2021 Jun;218(6)

Department of Pathology, Committees on Immunology and Cancer Biology, The University of Chicago, Chicago, IL.

Gaining a mechanistic understanding of the expansion and maturation program of natural killer (NK) cells will provide opportunities for harnessing their inflammation-inducing and oncolytic capacity for therapeutic purposes. Here, we demonstrated that ID2, a transcriptional regulatory protein constitutively expressed in NK cells, supports NK cell effector maturation by controlling the amplitude and temporal dynamics of the transcription factor TCF1. TCF1 promotes immature NK cell expansion and restrains differentiation. The increased TCF1 expression in ID2-deficient NK cells arrests their maturation and alters cell surface receptor expression. Moreover, TCF1 limits NK cell functions, such as cytokine-induced IFN-γ production and the ability to clear metastatic melanoma in ID2-deficient NK cells. Our data demonstrate that ID2 sets a threshold for TCF1 during NK cell development, thus controlling the balance of immature and terminally differentiated cells that support future NK cell responses.
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http://dx.doi.org/10.1084/jem.20202032DOI Listing
June 2021

It's a Phase That EBF1 Is Going Through.

Authors:
Barbara L Kee

Immunity 2020 Dec;53(6):1123-1125

Department of Pathology, Committees on Immunology, Cancer Biology, Genetics, Genomics and Systems Biology, University of Chicago, 924 E. 57(th) St., Chicago, IL 60637, USA. Electronic address:

EBF1 is a pioneer transcription factor involved in B lymphocyte specification. In this issue of Immunity, Wang et al. localize EBF1's pioneering activity to a prion-like domain that mediates recruitment of the nucleosome remodeler Brg1 and FUS-assisted liquid-liquid phase separation.
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http://dx.doi.org/10.1016/j.immuni.2020.11.013DOI Listing
December 2020

Combinatorial ETS1-dependent control of oncogenic NOTCH1 enhancers in T-cell leukemia.

Blood Cancer Discov 2020 Sep;1(2):178-197

Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI.

Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis, but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and points to Ets1-mediated enucleation of Notch-Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482717PMC
September 2020

The transcription factor BCL-6 controls early development of innate-like T cells.

Nat Immunol 2020 09 27;21(9):1058-1069. Epub 2020 Jul 27.

Institute for Fundamental Biomedical Research, BSRC Alexander Fleming, Vari, Greece.

Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence of Bcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, including Zbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development.
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http://dx.doi.org/10.1038/s41590-020-0737-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442690PMC
September 2020

Transcriptional regulation of natural killer cell development and maturation.

Adv Immunol 2020 26;146:1-28. Epub 2020 Feb 26.

Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL, United States.

Natural killer cells are lymphocytes that respond rapidly to intracellular pathogens or cancer/stressed cells by producing pro-inflammatory cytokines or chemokines and by killing target cells through direct cytolysis. NK cells are distinct from B and T lymphocytes in that they become activated through a series of broadly expressed germ line encoded activating and inhibitory receptors or through the actions of inflammatory cytokines. They are the founding member of the innate lymphoid cell family, which mirror the functions of T lymphocytes, with NK cells being the innate counterpart to CD8 T lymphocytes. Despite the functional relationship between NK cells and CD8 T cells, the mechanisms controlling their specification, differentiation and maturation are distinct, with NK cells emerging from multipotent lymphoid progenitors in the bone marrow under the control of a unique transcriptional program. Over the past few years, substantial progress has been made in understanding the developmental pathways and the factors involved in generating mature and functional NK cells. NK cells have immense therapeutic potential and understanding how to acquire large numbers of functional cells and how to endow them with potent activity to control hematopoietic and non-hematopoietic malignancies and autoimmunity is a major clinical goal. In this review, we examine basic aspects of conventional NK cell development in mice and humans and discuss multiple transcription factors that are known to guide the development of these cells.
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http://dx.doi.org/10.1016/bs.ai.2020.01.001DOI Listing
February 2020

Ezh2 Represses Transcription of Innate Lymphoid Genes in B Lymphocyte Progenitors and Maintains the B-2 Cell Fate.

J Immunol 2020 04 24;204(7):1760-1769. Epub 2020 Feb 24.

Committee on Immunology, The University of Chicago, Chicago, IL 60657;

Lymphocyte lineage specification and commitment requires the activation of lineage-specific genes and repression of alternative lineage genes, respectively. The mechanisms governing alternative lineage gene repression and commitment in lymphocytes are largely unknown. In this study, we demonstrate that Ezh2, which represses gene expression through methylation of histone 3 lysine 27, was essential for repression of numerous genes, including genes encoding innate lymphocyte transcription factors, specifically in murine B lymphocyte progenitors, but these cells maintained their B lymphocyte identity. However, adult Ezh2-deficient B lymphocytes expressed , which encodes an RNA-binding protein associated with fetal hematopoietic gene expression programs, and these cells acquired a fetal B-1 lymphocyte phenotype in vitro and in vivo. Therefore, Ezh2 coordinates the repression of multiple gene programs in B lymphocytes and maintains the adult B-2 cell fate.
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http://dx.doi.org/10.4049/jimmunol.1901188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344269PMC
April 2020

Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf.

Cell Rep 2019 10;29(5):1203-1220.e7

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

The basic leucine zipper transcription factor activating transcription factor-like (Batf) contributes to transcriptional programming of multiple effector T cells and is required for T helper 17 (Th17) and T follicular helper (Tfh) cell development. Here, we examine mechanisms by which Batf initiates gene transcription in developing effector CD4 T cells. We find that, in addition to its pioneering function, Batf controls developmentally regulated recruitment of the architectural factor Ctcf to promote chromatin looping that is associated with lineage-specific gene transcription. The chromatin-organizing actions of Batf are largely dependent on Ets1, which appears to be indispensable for the Batf-dependent recruitment of Ctcf. Moreover, most of the Batf-dependent sites to which Ctcf is recruited lie outside of activating protein-1-interferon regulatory factor (Ap-1-Irf) composite elements (AICEs), indicating that direct involvement of Batf-Irf complexes is not required. These results identify a cooperative role for Batf, Ets1, and Ctcf in chromatin reorganization that underpins the transcriptional programming of effector T cells.
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http://dx.doi.org/10.1016/j.celrep.2019.09.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182170PMC
October 2019

Cryptic activation of an Irf8 enhancer governs cDC1 fate specification.

Nat Immunol 2019 09 12;20(9):1161-1173. Epub 2019 Aug 12.

Department of Pathology and Immunology, Washington University in St Louis, School of Medicine, St Louis, MO, USA.

Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.
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http://dx.doi.org/10.1038/s41590-019-0450-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707878PMC
September 2019

Cutting Edge: Lymphomyeloid-Primed Progenitor Cell Fates Are Controlled by the Transcription Factor Tal1.

J Immunol 2019 05 8;202(10):2837-2842. Epub 2019 Apr 8.

Department of Pathology, The University of Chicago, Chicago, IL 60637;

Lymphoid specification is the process by which hematopoietic stem cells (HSCs) and their progeny become restricted to differentiation through the lymphoid lineages. The basic helix-loop-helix transcription factors E2A and Lyl1 form a complex that promotes lymphoid specification. In this study, we demonstrate that Tal1, a Lyl1-related basic helix-loop-helix transcription factor that promotes T acute lymphoblastic leukemia and is required for HSC specification, erythropoiesis, and megakaryopoiesis, is a negative regulator of murine lymphoid specification. We demonstrate that Tal1 limits the expression of multiple E2A target genes in HSCs and controls the balance of myeloid versus T lymphocyte differentiation potential in lymphomyeloid-primed progenitors. Our data provide insight into the mechanisms controlling lymphocyte specification and may reveal a basis for the unique functions of Tal1 and Lyl1 in T acute lymphoblastic leukemia.
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http://dx.doi.org/10.4049/jimmunol.1801220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504590PMC
May 2019

Transcription factor ID2 prevents E proteins from enforcing a naïve T lymphocyte gene program during NK cell development.

Sci Immunol 2018 04;3(22)

Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60657, USA.

All innate lymphoid cells (ILCs) require the small helix-loop-helix transcription factor ID2, but the functions of ID2 are not well understood in these cells. We show that mature natural killer (NK) cells, the prototypic ILCs, developed in mice lacking ID2 but remained as precursor CD27CD11b cells that failed to differentiate into CD27CD11b cytotoxic effectors. We show that ID2 limited chromatin accessibility at E protein binding sites near naïve T lymphocyte-associated genes including multiple chemokine receptors, cytokine receptors, and signaling molecules and altered the NK cell response to inflammatory cytokines. In the absence of ID2, CD27CD11b NK cells expressed ID3, a helix-loop-helix protein associated with naïve T cells, and they transitioned from a CD8 memory precursor-like to a naïve-like chromatin accessibility state. We demonstrate that ID3 was required for the development of ID2-deficient NK cells, indicating that completely unfettered E protein function is incompatible with NK cell development. These data solidify the roles of ID2 and ID3 as mediators of effector and naïve gene programs, respectively, and revealed a critical role for ID2 in promoting a chromatin state and transcriptional program in CD27CD11b NK cells that supports cytotoxic effector differentiation and cytokine responses.
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http://dx.doi.org/10.1126/sciimmunol.aao2139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750718PMC
April 2018

Transcriptional and epigenetic regulation of innate-like T lymphocyte development.

Curr Opin Immunol 2018 04 14;51:39-45. Epub 2018 Feb 14.

Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60657, USA. Electronic address:

Invariant Natural Killer T (iNKT) cells are a heterogeneous innate T cell population that recognizes lipid antigens. Despite the monospecific nature of their T cell receptor, iNKT cells differentiate into stable sublineages during thymic development, before foreign antigen encounter. How iNKT cell subsets acquire and maintain their functional programs is a central question in innate lymphocyte biology. Global transcriptional and epigenetic profiling of iNKT subsets has provided insights into the internal wiring of these subsets that defines their identity. Comparison of the iNKT transcriptional programs with those of other adaptive and innate lymphocyte lineages revealed common core regulatory circuits that may dictate effector functions. In this review, we summarize recent advances on the molecular mechanisms involved in iNKT cell development.
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http://dx.doi.org/10.1016/j.coi.2018.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943139PMC
April 2018

Lnc'ing Id2 to ILC1.

Immunity 2017 09;47(3):389-390

Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

The transcriptional repressor Id2 is constitutively expressed in all innate lymphoid cells (ILCs) and is required for their development. In this issue of Immunity, Mowel et al. (2017) demonstrate that Id2 expression is regulated by a cell type-specific cis-regulatory element in group 1 ILCs that is demarcated by a long non-coding RNA.
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http://dx.doi.org/10.1016/j.immuni.2017.08.019DOI Listing
September 2017

EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints.

J Immunol 2017 06 10;198(12):4682-4691. Epub 2017 May 10.

Committee on Immunology, The University of Chicago, Chicago, IL 60637;

The histone methyltransferase EZH2 is required for B and T cell development; however, the molecular mechanisms underlying this requirement remain elusive. In a murine model of lymphoid-specific EZH2 deficiency we found that EZH2 was required for proper development of adaptive, but not innate, lymphoid cells. In adaptive lymphoid cells EZH2 prevented the premature expression of and the consequent stabilization of p53, an effector of the pre-Ag receptor checkpoints. Deletion of in EZH2-deficient lymphocytes prevented p53 stabilization, extended lymphocyte survival, and restored differentiation resulting in the generation of mature B and T lymphocytes. Our results uncover a crucial role for EZH2 in adaptive lymphocytes to control the developmental timing of effectors of the pre-Ag receptor checkpoints.
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http://dx.doi.org/10.4049/jimmunol.1700319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527689PMC
June 2017

Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale.

Eur J Immunol 2017 03;47(3):454-457

Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL, USA.

The mammalian Target of Rapamycin (mTOR) protein controls the machinery necessary for T-cell activation, differentiation, and memory formation, as a component of mTOR complex 1 (mTORC1) and mTORC2, which function both downstream and upstream of AKT. Invariant natural killer T (iNKT) cells are a unique T-cell subset that exist in a primed state, capable of rapid activation, and produce large quantities of cytokines. iNKT-cell effector differentiation is dependent on the mTORC1 complex; however, the requirements for mTORC2 in iNKT cells have been controversial. In this issue, Sklarz et al. [Eur. J. Immunol. 2017. 47: 516-526] provide a careful analysis of the requirements for the mTORC2 component Rictor in iNKT cells, providing a new twist in this unfolding tale. The authors demonstrate that Rictor is required for iNKT-cell proliferation and survival during the key stage of intrathymic expansion and that Rictor supports the development of NKT17 cells, an effector subset which depends on the transcription factor RORγt and produces interleukin (IL)-17, in both the thymus and the lung. IL-4-producing NKT2 cells develop in the absence of Rictor but the cytotoxic potential of iNKT cells is Rictor-dependent.
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http://dx.doi.org/10.1002/eji.201746921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582540PMC
March 2017

Murine thymic NK cells are distinct from ILC1s and have unique transcription factor requirements.

Eur J Immunol 2017 05 13;47(5):800-805. Epub 2017 Apr 13.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Group 1 innate lymphoid cells include natural killer (NK) cells and ILC1s, which mediate the response to intracellular pathogens. Thymic NK (tNK) cells were described with hybrid features of immature NK cells and ILC1 but whether these cells are related to NK cells or ILC1 has not been fully investigated. We report that murine tNK cells expressed the NK-cell associated transcription factor EOMES and developed independent of the essential ILC1 factor TBET, confirming their placement within the NK lineage. Moreover, tNK cells resemble NK cells rather than ILC1 in their requirements for the E protein transcription factor inhibitor ID2. We provide further insight into the mechanisms governing tNK-cell development by showing that the transcription factor ETS1 prevented tNK cell acquisition of the conventional NK-cell maturation markers CD11b and KLRG1. Our data reveal few ILC1 in the thymus and clarify the identity and developmental requirements of tNK cells.
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http://dx.doi.org/10.1002/eji.201646871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662841PMC
May 2017

Development of innate lymphoid cells.

Nat Immunol 2016 06;17(7):775-82

Committees on Immunology and Cancer Biology, Department of Pathology, The University of Chicago, Chicago, Illinois, USA.

Innate lymphoid cells (ILCs) are a family of immune effector cells that have important roles in host defense, metabolic homeostasis and tissue repair but can also contribute to inflammatory diseases such as asthma and colitis. These cells can be categorized into three groups on the basis of the transcription factors that direct their function and the cytokines they produce, which parallel the effector functions of T lymphocytes. The hierarchy of cell-fate-restriction events that occur as common lymphoid progenitors become committed to each of the ILC lineages further underscores the relationship between these innate immune cells and T lymphocytes. In this Review we discuss the developmental program of ILCs and transcription factors that guide ILC lineage specification and commitment.
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http://dx.doi.org/10.1038/ni.3481DOI Listing
June 2016

The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2.

J Exp Med 2016 05 11;213(5):687-96. Epub 2016 Apr 11.

Committee on Immunology, The University of Chicago, Chicago, IL 60637 Department of Pathology, The University of Chicago, Chicago, IL 60637

Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33-induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development.
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http://dx.doi.org/10.1084/jem.20150851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854726PMC
May 2016

Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells.

J Immunol 2016 Feb 18;196(4):1550-7. Epub 2016 Jan 18.

Committee on Immunology, University of Chicago, Chicago, IL 60637; Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637; Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637;

The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria, for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. In this study, we investigate the contribution of two T cell subsets, Th17 and follicular helper T (Tfh), to arthritis and how microbiota modulates their differentiation. Using genetic approaches, we demonstrate that IL-17 is dispensable for arthritis. Antibiotic treatment inhibits disease in IL-17-deficient animals, suggesting that the gut microbiota regulates arthritis independent of Th17 cells. In contrast, conditional deletion of Bcl6 in T cells blocks Tfh cell differentiation and arthritis development. Furthermore, Tfh cell differentiation is defective in antibiotic-treated mice. Taken together, we conclude that gut microbiota regulates arthritis through Tfh but not Th17 cells. These findings have implications in our understanding of how environmental factors contribute to the development of autoimmune diseases.
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http://dx.doi.org/10.4049/jimmunol.1501904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744513PMC
February 2016

Analysis of GzmbCre as a Model System for Gene Deletion in the Natural Killer Cell Lineage.

PLoS One 2015 29;10(4):e0125211. Epub 2015 Apr 29.

Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, Illinois, United States of America; Committee on Immunology, University of Chicago, Chicago, Illinois, United States of America; Committee on Cancer Biology, University of Chicago, Chicago, Illinois, United States of America; Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.

The analysis of gene function in mature and activated natural killer cells has been hampered by the lack of model systems for Cre-mediated recombination in these cells. Here we have investigated the utility of GzmbCre for recombination of loxp sequences in these cells predicated on the observation that Gzmb mRNA is highly expressed in mature and activated natural killer cells. Using two different reporter strains we determined that gene function could be investigated in mature natural killer cells after GzmbCre mediated recombination in vitro in conditions that lead to natural killer cell activation such as in the cytokine combination of interleukin 2 and interleukin 12. We demonstrated the utility of this model by creating GzmbCre;Rosa26IKKbca mice in which Cre-mediated recombination resulted in expression of constitutively active IKKβ, which results in activation of the NFκB transcription factor. In vivo and in vitro activation of IKKβ in natural killer cells revealed that constitutive activation of this pathway leads to natural killer cell hyper-activation and altered morphology. As a caveat to the use of GzmbCre we found that this transgene can lead to recombination in all hematopoietic cells the extent of which varies with the particular loxp flanked allele under investigation. We conclude that GzmbCre can be used under some conditions to investigate gene function in mature and activated natural killer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125211PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414598PMC
January 2016

Innate Lymphoid Cells Control Early Colonization Resistance against Intestinal Pathogens through ID2-Dependent Regulation of the Microbiota.

Immunity 2015 Apr;42(4):731-43

Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA; Institute of Biophysics and The University of Chicago joint Group for Immunotherapy, Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.immuni.2015.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725053PMC
April 2015

The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation.

J Exp Med 2015 May 20;212(5):793-807. Epub 2015 Apr 20.

Committee on Immunology, Committee on Molecular Pathogenesis and Molecular Medicine, and Department of Pathology, The University of Chicago, Chicago, IL 60637 Committee on Immunology, Committee on Molecular Pathogenesis and Molecular Medicine, and Department of Pathology, The University of Chicago, Chicago, IL 60637

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.
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http://dx.doi.org/10.1084/jem.20141849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419352PMC
May 2015

Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the Notch signaling pathway.

J Immunol 2015 Apr 20;194(7):3191-200. Epub 2015 Feb 20.

Committee on Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637; Committee on Immunology, The University of Chicago, Chicago, IL 60637; Department of Pathology, The University of Chicago, Chicago, IL 60637

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.
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http://dx.doi.org/10.4049/jimmunol.1402443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369417PMC
April 2015

ID'ing innate and innate-like lymphoid cells.

Immunol Rev 2014 Sep;261(1):177-97

Committee on Immunology and Department of Pathology, The University of Chicago, Chicago, IL, USA.

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.
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http://dx.doi.org/10.1111/imr.12203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159719PMC
September 2014

Sox4 B-lymphocyte progenitors.

Authors:
Barbara L Kee

Blood 2014 Jun;123(26):4009-10

THE UNIVERSITY OF CHICAGO.

In this issue of Blood, Mallampati et al provide mechanistic insight into the functions of the transcription factor Sox4 in pro-B lymphocytes using both gain-of-function and loss-of-function approaches combined with global gene expression and genome-wide transcription factor binding analysis.
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http://dx.doi.org/10.1182/blood-2014-05-574178DOI Listing
June 2014

Essential functions for ID proteins at multiple checkpoints in invariant NKT cell development.

J Immunol 2013 Dec 15;191(12):5973-83. Epub 2013 Nov 15.

Department of Pathology, University of Chicago, Chicago, IL 60637;

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.
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http://dx.doi.org/10.4049/jimmunol.1301521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864619PMC
December 2013

Fingerprinting ikaros.

Nat Immunol 2013 Oct;14(10):1034-5

Department of Medicine, The University of Chicago, Chicago, Illinois, USA.

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http://dx.doi.org/10.1038/ni.2709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197131PMC
October 2013

E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment.

Blood 2013 Feb 7;121(9):1534-42. Epub 2013 Jan 7.

Committees on Cancer Biology and. Immunology, Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.

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 small interfering RNA-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 to restrain self-renewal and to prevent an arrest in differentiation.
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http://dx.doi.org/10.1182/blood-2012-08-449447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587319PMC
February 2013

Inhibitors of DNA binding proteins restrict T cell potential by repressing Notch1 expression in Flt3-negative common lymphoid progenitors.

J Immunol 2012 Oct 12;189(8):3822-30. Epub 2012 Sep 12.

Institut Pasteur, Unité de Lymphopoièse, 75015 Paris, France.

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.
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http://dx.doi.org/10.4049/jimmunol.1103723DOI Listing
October 2012

Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1.

Immunity 2012 Jun 17;36(6):921-32. Epub 2012 May 17.

Committee on Immunology, The University of Chicago, Chicago, IL 60615, USA.

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.
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http://dx.doi.org/10.1016/j.immuni.2012.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389314PMC
June 2012