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Barbara Lynne Kee

TitleProfessor
InstitutionUniversity of Chicago
DepartmentPathology
AddressChicago IL 60637
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    Transcriptional Control of Innate and Adaptive Lymphoid Development and Transformation

    The execution of an effective immune response with minimal immune-mediated disease requires appropriate control of the development and function of adaptive and innate components of the immune system. B and T lymphocytes are the cells that mediate adaptive immunity; they are highly antigen specific but require substantial expansion and activation prior to promoting an effective immune response. In contrast, natural killer (NK) cells, innate-like T lymphocytes, and the recently identified innate lymphoid cells (ILCs) are lymphocytes that function in innate immunity; they acquire their effector properties during their development and are poised to rapidly confront invading pathogens. All immune system cells develop from a common hematopoietic stem cell (HSC) whose differentiation pathway is controlled in part by the activation and repression of lineage specific gene programs. Our laboratory is interested in understanding how these transcriptional programs are wired and how alterations in these pathways lead to disease such as autoimmunity, asthma and acute leukemia.

    The E protein class of basic helix-loop-helix (bHLH) transcription factors and their antagonists, the ID proteins, play fundamental roles in the choice between adaptive and innate lymphoid differentiation and they control the precise effector functions exhibited by these cells. Failure to properly control the activity of these proteins leads to immune deficiencies and cancer. The E protein E2A is required for development of B and T lymphocytes due to direct regulation of critical transcriptional networks that specify these lineages from HSCs and multipotent progenitors. Despite a severe T lymphocyte immune deficiency in E2A-deficient mice, the mice develop a disease similar to T lymphocyte acute lymphoblastic leukemia (T-ALL), and the human disease is characterized by recurrent mutations that affect E protein function. We identified a transcriptional cascade involving the transcription factors Notch1 and LEF1 as being critical for leukemia cell survival and we are working toward an understanding of how these transcription factors contribute to both immune deficiency and leukemogenesis.

    ID2 and ID3 control the development and effector fate of innate lymphoid cells including NK cells, ILCs and NKT cells. Our laboratory has focused on understanding how ID protein expression is regulated in innate lymphoid cells and how the targets of the E protein transcription factors control adaptive and innate lymphoid cell differentiation. Our recent studies led to the identification of ETS1 as a critical regulator of ID2 that promotes NK cell and ILC differentiation, and we are working toward an understanding of how ETS1 and ID2 cooperate to control NK cell maturation and effector function.


    Collapse Biography 
    Collapse education and training
    University of Toronto, Toronto, CanadaB.S.06/1989Immunology
    University of Toronto, Toronto, CanadaPh.D. 01/1995Immunology
    The Salk Institute, La Jolla, CAPostdoc03/1996Transcription
    University of California, San Diego, La Jolla, CAPostdoc06/2001Transcription/Immunology

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    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Pham D, Moseley CE, Gao M, Savic D, Winstead CJ, Sun M, Kee BL, Myers RM, Weaver CT, Hatton RD. Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf. Cell Rep. 2019 Oct 29; 29(5):1203-1220.e7. PMID: 31665634.
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    2. Durai V, Bagadia P, Granja JM, Satpathy AT, Kulkarni DH, Davidson JT, Wu R, Patel SJ, Iwata A, Liu TT, Huang X, Briseño CG, Grajales-Reyes GE, Wöhner M, Tagoh H, Kee BL, Newberry RD, Busslinger M, Chang HY, Murphy TL, Murphy KM. Cryptic activation of an Irf8 enhancer governs cDC1 fate specification. Nat Immunol. 2019 09; 20(9):1161-1173. PMID: 31406378.
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    3. de Pooter RF, Dias S, Chowdhury M, Bartom ET, Okoreeh MK, Sigvardsson M, Kee BL. Cutting Edge: Lymphomyeloid-Primed Progenitor Cell Fates Are Controlled by the Transcription Factor Tal1. J Immunol. 2019 May 15; 202(10):2837-2842. PMID: 30962294.
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    4. Zook EC, Li ZY, Xu Y, de Pooter RF, Verykokakis M, Beaulieu A, Lasorella A, Maienschein-Cline M, Sun JC, Sigvardsson M, Kee BL. Transcription factor ID2 prevents E proteins from enforcing a naïve T lymphocyte gene program during NK cell development. Sci Immunol. 2018 04 27; 3(22). PMID: 29703840.
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    5. Verykokakis M, Kee BL. Transcriptional and epigenetic regulation of innate-like T lymphocyte development. Curr Opin Immunol. 2018 04; 51:39-45. PMID: 29452898.
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    6. Sun M, Kee BL. Lnc'ing Id2 to ILC1. Immunity. 2017 09 19; 47(3):389-390. PMID: 28930650.
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    7. Jacobsen JA, Woodard J, Mandal M, Clark MR, Bartom ET, Sigvardsson M, Kee BL. EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints. J Immunol. 2017 06 15; 198(12):4682-4691. PMID: 28490575.
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    8. Gabrielli S, Sun M, Bell A, Zook EC, de Pooter RF, Zamai L, Kee BL. Murine thymic NK cells are distinct from ILC1s and have unique transcription factor requirements. Eur J Immunol. 2017 05; 47(5):800-805. PMID: 28276053.
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    9. Verykokakis M, Kee BL. Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale. Eur J Immunol. 2017 03; 47(3):454-457. PMID: 28295259.
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    10. Zook EC, Kee BL. Development of innate lymphoid cells. Nat Immunol. 2016 06 21; 17(7):775-82. PMID: 27328007.
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    11. Zook EC, Ramirez K, Guo X, van der Voort G, Sigvardsson M, Svensson EC, Fu YX, Kee BL. The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2. J Exp Med. 2016 05 02; 213(5):687-96. PMID: 27069114.
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    12. Block KE, Zheng Z, Dent AL, Kee BL, Huang H. Gut Microbiota Regulates K/BxN Autoimmune Arthritis through Follicular Helper T but Not Th17 Cells. J Immunol. 2016 Feb 15; 196(4):1550-7. PMID: 26783341.
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    13. Krishnamoorthy V, Carr T, de Pooter RF, Emanuelle AO, Gounari F, Kee BL. Correction: Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the notch signaling pathway. J Immunol. 2015 Jun 15; 194(12):6191. PMID: 26048968.
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    14. Xu Y, Evaristo C, Alegre ML, Gurbuxani S, Kee BL. Analysis of GzmbCre as a Model System for Gene Deletion in the Natural Killer Cell Lineage. PLoS One. 2015; 10(4):e0125211. PMID: 25923440.
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    15. Guo X, Liang Y, Zhang Y, Lasorella A, Kee BL, Fu YX. Innate Lymphoid Cells Control Early Colonization Resistance against Intestinal Pathogens through ID2-Dependent Regulation of the Microbiota. Immunity. 2015 Apr 21; 42(4):731-43. PMID: 25902484.
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    16. Carr T, Krishnamoorthy V, Yu S, Xue HH, Kee BL, Verykokakis M. The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation. J Exp Med. 2015 May 04; 212(5):793-807. PMID: 25897173.
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    17. Xu W, Domingues RG, Fonseca-Pereira D, Ferreira M, Ribeiro H, Lopez-Lastra S, Motomura Y, Moreira-Santos L, Bihl F, Braud V, Kee B, Brady H, Coles MC, Vosshenrich C, Kubo M, Di Santo JP, Veiga-Fernandes H. NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep. 2015 Mar 31; 10(12):2043-54. PMID: 25801035.
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    18. Krishnamoorthy V, Carr T, de Pooter RF, Emanuelle AO, Akinola EO, Gounari F, Kee BL. Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the Notch signaling pathway. J Immunol. 2015 Apr 01; 194(7):3191-200. PMID: 25710912.
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    19. Verykokakis M, Zook EC, Kee BL. ID'ing innate and innate-like lymphoid cells. Immunol Rev. 2014 Sep; 261(1):177-97. PMID: 25123285.
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    20. Kee BL. Sox4 B-lymphocyte progenitors. Blood. 2014 Jun 26; 123(26):4009-10. PMID: 24970928.
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    21. Verykokakis M, Krishnamoorthy V, Iavarone A, Lasorella A, Sigvardsson M, Kee BL. Essential functions for ID proteins at multiple checkpoints in invariant NKT cell development. J Immunol. 2013 Dec 15; 191(12):5973-83. PMID: 24244015.
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    22. Gounari F, Kee BL. Fingerprinting ikaros. Nat Immunol. 2013 Oct; 14(10):1034-5. PMID: 24048134.
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    23. Xu W, Carr T, Ramirez K, McGregor S, Sigvardsson M, Kee BL. E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood. 2013 Feb 28; 121(9):1534-42. PMID: 23297135.
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    24. Pereira de Sousa A, Berthault C, Granato A, Dias S, Ramond C, Kee BL, Cumano A, Vieira P. Inhibitors of DNA binding proteins restrict T cell potential by repressing Notch1 expression in Flt3-negative common lymphoid progenitors. J Immunol. 2012 Oct 15; 189(8):3822-30. PMID: 22972921.
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    25. Ramirez K, Chandler KJ, Spaulding C, Zandi S, Sigvardsson M, Graves BJ, Kee BL. Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1. Immunity. 2012 Jun 29; 36(6):921-32. PMID: 22608498.
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    26. Mandal M, Powers SE, Maienschein-Cline M, Bartom ET, Hamel KM, Kee BL, Dinner AR, Clark MR. Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat Immunol. 2011 Oct 30; 12(12):1212-20. PMID: 22037603.
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    27. Kee BL. A comprehensive transcriptional landscape of human hematopoiesis. Cell Stem Cell. 2011 Feb 04; 8(2):122-4. PMID: 21295265.
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    28. Gómez-del Arco P, Kashiwagi M, Jackson AF, Naito T, Zhang J, Liu F, Kee B, Vooijs M, Radtke F, Redondo JM, Georgopoulos K. Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis. Immunity. 2010 Nov 24; 33(5):685-98. PMID: 21093322.
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    29. de Pooter RF, Kee BL. E proteins and the regulation of early lymphocyte development. Immunol Rev. 2010 Nov; 238(1):93-109. PMID: 20969587.
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    30. De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cavé H, Dastugue N, Raimondi S, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med. 2010 Nov; 16(11):1321-7. PMID: 20972433.
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    31. Tran AH, Berger A, Wu GE, Kee BL, Paige CJ. Early B-cell factor regulates the expression of Hemokinin-1 in the olfactory epithelium and differentiating B lymphocytes. J Neuroimmunol. 2011 Mar; 232(1-2):41-50. PMID: 20965576.
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    32. Verykokakis M, Boos MD, Bendelac A, Kee BL. SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity. 2010 Aug 27; 33(2):203-15. PMID: 20674402.
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    33. Ramirez K, Kee BL. Multiple hats for natural killers. Curr Opin Immunol. 2010 Apr; 22(2):193-8. PMID: 20335012.
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    34. Verykokakis M, Boos MD, Bendelac A, Adams EJ, Pereira P, Kee BL. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor protein-dependent "innate" gammadelta T cells. PLoS One. 2010 Feb 19; 5(2):e9303. PMID: 20174563.
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    35. Mandal M, Powers SE, Ochiai K, Georgopoulos K, Kee BL, Singh H, Clark MR. Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development. Nat Immunol. 2009 Oct; 10(10):1110-7. PMID: 19734904.
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    36. Gao J, Graves S, Koch U, Liu S, Jankovic V, Buonamici S, El Andaloussi A, Nimer SD, Kee BL, Taichman R, Radtke F, Aifantis I. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell. 2009 Jun 05; 4(6):548-58. PMID: 19497283.
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    37. Kee BL, Dias S. A s-myly route toward lymphoid differentiation. Immunity. 2009 Apr 17; 30(4):474-6. PMID: 19371711.
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    38. Kee BL. E and ID proteins branch out. Nat Rev Immunol. 2009 Mar; 9(3):175-84. PMID: 19240756.
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    39. Dias S, Xu W, McGregor S, Kee B. Transcriptional regulation of lymphocyte development. Curr Opin Genet Dev. 2008 Oct; 18(5):441-8. PMID: 18775782.
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    40. Dias S, Månsson R, Gurbuxani S, Sigvardsson M, Kee BL. E2A proteins promote development of lymphoid-primed multipotent progenitors. Immunity. 2008 Aug 15; 29(2):217-27. PMID: 18674933.
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    41. Bhalla S, Spaulding C, Brumbaugh RL, Zagort DE, Massari ME, Murre C, Kee BL. differential roles for the E2A activation domains in B lymphocytes and macrophages. J Immunol. 2008 Feb 01; 180(3):1694-703. PMID: 18209066.
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    42. Boos MD, Ramirez K, Kee BL. Extrinsic and intrinsic regulation of early natural killer cell development. Immunol Res. 2008; 40(3):193-207. PMID: 18266115.
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    43. Molinero LL, Zhou P, Wang Y, Harlin H, Kee B, Abraham C, Alegre ML. Epidermal Langerhans cells promote skin allograft rejection in mice with NF-kappa B-impaired T cells. Am J Transplant. 2008 Jan; 8(1):21-31. PMID: 18021281.
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    44. Spaulding C, Reschly EJ, Zagort DE, Yashiro-Ohtani Y, Beverly LJ, Capobianco A, Pear WS, Kee BL. Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas. Blood. 2007 Oct 01; 110(7):2650-8. PMID: 17585052.
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    45. Nutt SL, Kee BL. The transcriptional regulation of B cell lineage commitment. Immunity. 2007 Jun; 26(6):715-25. PMID: 17582344.
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    46. Boos MD, Yokota Y, Eberl G, Kee BL. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med. 2007 May 14; 204(5):1119-30. PMID: 17452521.
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    47. Welner RS, Pelayo R, Garrett KP, Chen X, Perry SS, Sun XH, Kee BL, Kincade PW. Interferon-producing killer dendritic cells (IKDCs) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors. Blood. 2007 Jun 01; 109(11):4825-931. PMID: 17317852.
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    48. Xu W, Kee BL. Growth factor independent 1B (Gfi1b) is an E2A target gene that modulates Gata3 in T-cell lymphomas. Blood. 2007 May 15; 109(10):4406-14. PMID: 17272506.
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    49. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML, Kee BL, Ferrando A, Miele L, Aifantis I. Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med. 2007 Jan; 13(1):70-7. PMID: 17173050.
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    50. Reschly EJ, Spaulding C, Vilimas T, Graham WV, Brumbaugh RL, Aifantis I, Pear WS, Kee BL. Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms. Blood. 2006 May 15; 107(10):4115-21. PMID: 16449526.
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    51. Kee BL. Id3 induces growth arrest and caspase-2-dependent apoptosis in B lymphocyte progenitors. J Immunol. 2005 Oct 01; 175(7):4518-27. PMID: 16177095.
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    52. Friedrich ML, Wen BG, Bain G, Kee BL, Katayama C, Murre C, Hedrick SM, Walsh CM. DRAK2, a lymphoid-enriched DAP kinase, regulates the TCR activation threshold during thymocyte selection. Int Immunol. 2005 Nov; 17(11):1379-90. PMID: 16172133.
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    53. Nick McElhinny SA, Havener JM, Garcia-Diaz M, Juárez R, Bebenek K, Kee BL, Blanco L, Kunkel TA, Ramsden DA. A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Mol Cell. 2005 Aug 05; 19(3):357-66. PMID: 16061182.
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    54. Osborne BA, Kee BL. Lymphoid development: it's not 'all Greek to us' any more. Nat Immunol. 2005 Feb; 6(2):119-23. PMID: 15662436.
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    55. Kee BL. Helix-loop-helix proteins in lymphocyte lineage determination. Curr Top Microbiol Immunol. 2005; 290:15-27. PMID: 16480037.
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    56. Seet CS, Brumbaugh RL, Kee BL. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. J Exp Med. 2004 Jun 21; 199(12):1689-700. PMID: 15210745.
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    57. Perkins EJ, Kee BL, Ramsden DA. Histone 3 lysine 4 methylation during the pre-B to immature B-cell transition. Nucleic Acids Res. 2004; 32(6):1942-7. PMID: 15051812.
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    58. Kee BL, Bain G, Murre C. IL-7Ralpha and E47: independent pathways required for development of multipotent lymphoid progenitors. EMBO J. 2002 Jan 15; 21(1-2):103-13. PMID: 11782430.
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    59. Kee BL, Murre C. Transcription factor regulation of B lineage commitment. Curr Opin Immunol. 2001 Apr; 13(2):180-5. PMID: 11228411.
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    60. Kee BL, Rivera RR, Murre C. Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta. Nat Immunol. 2001 Mar; 2(3):242-7. PMID: 11224524.
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    61. Kee BL, Quong MW, Murre C. E2A proteins: essential regulators at multiple stages of B-cell development. Immunol Rev. 2000 Jun; 175:138-49. PMID: 10933599.
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    62. Kee BL, Murre C. Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12. J Exp Med. 1998 Aug 17; 188(4):699-713. PMID: 9705952.
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    63. Kee BL, Paige CJ. In vitro tracking of IL-7 responsiveness and gene expression during commitment of bipotent B-cell/macrophage progenitors. Curr Biol. 1996 Sep 01; 6(9):1159-69. PMID: 8805368.
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    64. Kee BL, Arias J, Montminy MR. Adaptor-mediated recruitment of RNA polymerase II to a signal-dependent activator. J Biol Chem. 1996 Feb 02; 271(5):2373-5. PMID: 8576192.
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    65. Marshall AJ, Kee BL, Paige CJ, Wu GE. Analysis of immunoglobulin gene rearrangement in fetal B-cell progenitors developing in vivo or in vitro. Ann N Y Acad Sci. 1995 Sep 29; 764:222-3. PMID: 7486527.
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    66. Kee BL, Paige CJ. In-vitro models of B-lineage commitment. Semin Immunol. 1995 Jun; 7(3):143-54. PMID: 7579201.
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    67. Kee BL, Paige CJ. Murine B cell development: commitment and progression from multipotential progenitors to mature B lymphocytes. Int Rev Cytol. 1995; 157:129-79. PMID: 7706019.
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    68. Kee BL, Cumano A, Iscove NN, Paige CJ. Stromal cell independent growth of bipotent B cell--macrophage precursors from murine fetal liver. Int Immunol. 1994 Mar; 6(3):401-7. PMID: 7514441.
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    69. Cumano A, Kee BL, Ramsden DA, Marshall A, Paige CJ, Wu GE. Development of B lymphocytes from lymphoid committed and uncommitted progenitors. Immunol Rev. 1994 Feb; 137:5-33. PMID: 8034337.
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    70. Kee BL, Paige CJ, Letarte M. Characterization of murine CD10, an endopeptidase expressed on bone marrow adherent cells. Int Immunol. 1992 Sep; 4(9):1041-7. PMID: 1390435.
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    71. Kee BL, Dadi HK, Tran-Paterson R, Quackenbush EJ, Andrulis IL, Letarte M. CD10 and CD44 genes of leukemic cells and malignant cell lines show no evidence of transformation-related alterations. J Cell Physiol. 1991 Sep; 148(3):414-20. PMID: 1833412.
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