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
2001
The Salk Institute
La Jolla, CA
Postdoc - Transcription
1996
University of Toronto
Toronto, Canada
Ph.D. - Immunology
1995
University of Toronto
Toronto, Canada
B.S. - Immunology
1989
Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T-ALL.
Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T-ALL. Leukemia. 2024 03; 38(3):491-501.
PMID: 38155245
TGF-ß Promotes the Postselection Thymic Development and Peripheral Function of IFN-?-Producing Invariant NKT cells.
TGF-ß Promotes the Postselection Thymic Development and Peripheral Function of IFN-?-Producing Invariant NKT cells. J Immunol. 2023 Nov 01; 211(9):1376-1384.
PMID: 37702745
Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia.
Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia. Clin Cancer Res. 2023 08 15; 29(16):3151-3161.
PMID: 37363966
Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation.
Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation. Immunity. 2023 07 11; 56(7):1451-1467.e12.
PMID: 37263273
Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia.
Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia. bioRxiv. 2023 Apr 25.
PMID: 37163059
Editorial: Molecular switches of the immune system: The E-protein/Id axis in hematopoietic development and function.
Editorial: Molecular switches of the immune system: The E-protein/Id axis in hematopoietic development and function. Front Immunol. 2022; 13:1062734.
PMID: 36405705
Genomic and Transcriptional Mechanisms Governing Innate-like T Lymphocyte Development.
Genomic and Transcriptional Mechanisms Governing Innate-like T Lymphocyte Development. J Immunol. 2022 07 15; 209(2):208-216.
PMID: 35821098
E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia.
E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia. Front Immunol. 2022; 13:885144.
PMID: 35514954
Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a-/- T Acute Lymphoblastic Leukemia.
Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a-/- T Acute Lymphoblastic Leukemia. Front Immunol. 2022; 13:845488.
PMID: 35371057
The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude.
The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude. J Exp Med. 2021 06 07; 218(6).
PMID: 33857289