Project Details
Description
PROJECT SUMMARY/ABSTRACT
Natural killer (NK) cells are innate lymphocytes that mediate cellular cytotoxicity against virally infected and
malignant cells. Upon activation, they also release chemokines and cytokines that help prime and coordinate the
adaptive immune response. Because of these functional properties, there is continued interest in developing NK
cell products for immunotherapy. However, this effort is hindered by our limited understanding of human NK cell
differentiation and the transcription factor networks that regulate this process. In work supported by current
K99/R00 funding, we generated a considerable amount of preliminary data comprehensively characterizing the
transcriptional and epigenetic landscapes in sorted NK and CD8+ T cell subsets isolated from cytomegalovirus
(CMV) seropositive donors. To complement these analyses, we performed flow cytometry-based analyses of
transcription factor expression and ChIP-seq on sorted peripheral blood NK cell subsets to construct transcription
factor networks that potentially regulate key steps in NK cell differentiation. The culmination of this work revealed
a central role for Bcl11b. This was completely unexpected given several detailed studies in mice showing that
Bcl11b expression is restricted to the T, NKT, and ILC2 lineages and acts to enforce T cell identity. Our
preliminary results also revealed a reciprocal relationship between Runx2 and Bcl11b, with Runx2 regulating a
set of transcription factors enriched in immature NK cells and Bcl11b regulating genes enriched throughout
canonical NK cell maturation and in adaptive NK cells exhibiting a T cell-like gene expression signature. In this
application we will test the hypothesis that Runx2 is a major hub that enforces the epigenetic identity of immature
CD56bright NK cells, while Bcl11b suppresses the Runx2-directed transcriptional program to drive canonical NK
cell differentiation, maturation, and cytotoxic effector function. We also posit that high levels of Bcl11b contribute
to the T cell-like features of CMV-induced adaptive NK cells.
We propose two independent aims to test our hypotheses. In the first aim, we will use overexpression
and knockdown strategies in sorted NK cell subsets to define the roles of Bcl11b and Runx2 during canonical
NK cell differentiation. These results will guide subsequent experiments designed to determine whether Bcl11b
overexpression in hematopoietic progenitor cells (HPCs) promotes NK cell maturation and effector function both
in vitro and after adoptive transfer into mice with established tumors. In the second aim, we will determine the
role of Bcl11b in promoting T cell-associated features of CMV-induced adaptive NK cells and test the hypothesis
that high levels of Bcl11b along with activating receptor and cytokine receptor stimulation drives adaptive NK cell
differentiation and maturation. We will also test the hypothesis that adaptive NK cells mediate superior antitumor
function in vivo relative to canonical NK cells. Results generated from this proposal will define the role of Bcl11b
in promoting canonical and adaptive NK cell differentiation, determine whether Bcl11b overexpression enhances
NK cell-mediated antitumor activity, and definitively test the antitumor function of adaptive NK cells.
Status | Active |
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Effective start/end date | 7/1/21 → 4/30/24 |
Funding
- National Heart, Lung, and Blood Institute: $310,000.00
- National Heart, Lung, and Blood Institute: $310,000.00
- National Heart, Lung, and Blood Institute: $310,000.00
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