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Expression of the transcription factor PLZF is suppressed in non-innate T cells and PLZF plays a critical role in basophil development and function in Th2 immunity

by
Sai Zhang
B.S. China Pharmaceutical University, 2011

Thesis advisor: Dr. Derek B. Sant’Angelo
Graduate Program in Microbiology and Molecular Genetics

CHINJ, Conference Room 3101
Child Health Institute of New Jersey
New Brunswick

Thursday, June 8, 2017
2:00 p.m.


Abstract

The transcription factor PLZF is one member of the BTB-ZF transcription factor family, which play critical roles in defining multiple lineages during the immune system development. PLZF, in particular, is shown to be essential for the development and effector functions of several immune cell subsets, including natural killer T cells, a subset of γδ T cells, innate lymphoid cell precursors, and mucosal-associated invariant T cells. These cells display “innate-like” features such as rapid response upon activation and ability to produce various effector cytokines. It has been shown that their potent effector program is controlled by the expression of the transcription factor PLZF. It is a common process that many lineage-defining transcription factors such as T-bet, GATA3, RORγt, and FoxP3, can be induced by activation during naïve T cell development, conferring the cells with plasticity and leading to Th1, Th2, Th17 and Treg differentiation. It is reasonable to propose that PLZF can be induced through activation in a similar fashion, especially natural killer T cells and γδ T cells are shown to be positively selected by strong T cell receptor-mediated signals during development in the thymus. In this study, we discovered that in contrary to popular hypothesis, PLZF expression was stably repressed in non-innate T cells and could not be induced via strong T cell receptor-mediated signaling. This discovery was also supported by the evidence of epigenetic silencing of the zbtb16 gene locus in non-innate T cells. Strict regulation of PLZF expression ensures its exclusive expression in certain types of immune cells. Using the PLZF-GFP reporter mice, we made the novel finding that PLZF was also expressed mouse basophils. Basophils are a rare subset of granulocytes that are involved in helminth infection and allergic reactions. Our results showed that in the absence of PLZF, basophils displayed developmental deficiency in the bone marrow and there was decreased number of mature basophils in the periphery. In terms of function, PLZF-deficient basophils were less sensitive to IgE or PMA/Ionomycin activation and produced less amount of IL-4 in vitro. Protease-induced Th2 responses mediated by basophils were impaired in the absence of PLZF in vivo. We also found that PLZF regulated IL-18 receptor expression on basophils and impacted their migration to the lung. In addition, our results revealed that another BTB-ZF gene, ThPOK, was co-expressed in basophils and impacted basophils function in Th2 response as well. Collectively, our study showed that PLZF expression was highly restricted and cannot be induced through T cell receptor-mediated signaling in non-innate T cells. Our result also revealed the novel finding of PLZF expression in basophils and it plays a critical role in regulating basophil effector function in Th2 immunity in mice.


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