Welcome to the Kee Lab!
Our lab is focused on understanding the transcriptional regulatory networks that control the development of innate and adaptive lymphoid cells and the mechanisms that control their homeostasis. 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 innate lymphoid cells (ILCs) are lymphocytes that acquire their effector properties during their development and are poised to rapidly confront invading pathogens. Over that past 20 years, multiple transcription factors have been shown to play a role in these developmental decisions but how these factors, and the underlying epigenetic state of the cells, coordinate to generate cells with distinct functional properties is not well understood.
To gain insight into these questions we have focused on two families of transcriptional regulators that are critical for proper innate and adaptive lymphoid development and whose dysregulated activities lead to profound immune deficiency or oncogenic transformation. We are working toward an understanding of how these factors operate in distinct cellular contexts in which they might promote similar or distinct gene programs. We study the basic helix-loop-helix transcription factors including 1) the E proteins, which are required for specification of lymphoid differentiation from hematopoietic stem cells and subsequently contribute to the initiation of the gene programs essential for B and T lymphocyte lineage specification; 2) the ID proteins, which antagonize E protein DNA binding and are required for NK cell and innate-like T lymphocytes to acquire their primed effector state and for differentiation into cytotoxic effectors; and 3) the E protein interacting protein Tal1, which opposes E protein driven lymphoid specification and functions as an oncogenic factor in T lineage acute lymphoblastic leukemia. The second family of transcription factors that we study are the ETS proteins, with a primary focus on ETS1. ETS1 is broadly expressed in innate and adaptive lymphoid cells and generally functions to suppress their activation. In NK cells, ETS1 is required to maintain the mature NK cell population and it limits their maturation and response to cytokine stimulation.
Current interests of the lab include:
- Determining the molecular basis for dysregulated NK and NKT cell maturation in the absence of ID proteins.
- Determine the mechanisms by which ETS1 contributes to NK cell and NKT cell effector maturation.
- Determine the mechanisms by which Tal1 controls lymphoid and innate lymphoid cell specification from multipotent progenitors.