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 California, San Diego
La Jolla, CA
Postdoc - Transcription/Immunology
The Salk Institute
La Jolla, CA
Postdoc - Transcription
University of Toronto
Ph.D. - Immunology
University of Toronto
B.S. - Immunology
Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf.
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.
Cryptic activation of an Irf8 enhancer governs cDC1 fate specification.
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.
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.
Lnc'ing Id2 to ILC1.
Sun M, Kee BL. Lnc'ing Id2 to ILC1. Immunity. 2017 09 19; 47(3):389-390.
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.
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.
Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale.
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.
Development of innate lymphoid cells.
Zook EC, Kee BL. Development of innate lymphoid cells. Nat Immunol. 2016 06 21; 17(7):775-82.