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.
University of Toronto
B.S. - Immunology
University of Toronto
Ph.D. - Immunology
The Salk Institute
La Jolla, CA
Postdoc - Transcription
University of California, San Diego
La Jolla, CA
Postdoc - Transcription/Immunology
EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints.
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.
Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2.
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.
Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development.
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.
Analysis of GzmbCre as a Model System for Gene Deletion in the Natural Killer Cell Lineage.
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.
E2A proteins promote development of lymphoid-primed multipotent progenitors.
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.
Lnc'ing Id2 to ILC1.
Sun M, Kee BL. Lnc'ing Id2 to ILC1. Immunity. 2017 09 19; 47(3):389-390.
Cutting Edge: Lymphomyeloid-Primed Progenitor Cell Fates Are Controlled by the Transcription Factor Tal1.
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.
Transcription factor ID2 prevents E proteins from enforcing a naïve T lymphocyte gene program during NK cell development.
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).
Transcriptional and epigenetic regulation of innate-like T lymphocyte development.
Verykokakis M, Kee BL. Transcriptional and epigenetic regulation of innate-like T lymphocyte development. Curr Opin Immunol. 2018 04; 51:39-45.
Murine thymic NK cells are distinct from ILC1s and have unique transcription factor requirements.
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.