During hematopoiesis, multilineage progenitor cells and the precursors are committed to individual hematopoietic lineages. In normal myelopoiesis, the immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells. However, under tumor burden, these IMCs differentiate into myeloid derived suppressor cells (MDSCs) result in an up-regulation of immune suppressive factors and pro-tumor effect. The development of normal or malignant is tightly controlled by endogenous signals such as transcription factors and epigenetic regulations. HDAC11 is the newest identified members of the histone deacetylase (HDAC) family. Previous study in our group had identified HDAC11 as a negative regulator of interleukin 10 (IL-10) production in antigen-presenting cells (APCs). However, the mechanisms of HDAC11 in regulating myeloid cells differentiation and function remained unclear.
We have uncovered for the first time that in the absence of HDAC11, upon LPS stimulation, neutrophils isolated form mice displays an over-production of pro-inflammatory cytokines such as TNF-alpha and IL-6. Strikingly, these HDAC11KO neutrophils showed a significantly higher migratory and phagocytosis activity, resulting from an overexpression of the migratory receptor and cytokine CXCR/L2. We have performed Chromatin Immunoprecipitation (ChIP) analysis on the neutrophils and discovered that HDAC11 was recruited to the promoter regulatory region of these genes we have identified. This part of data will be discussed mainly in chapter 2.
Not only does HDAC11 plays a crucial role in the neutrophil function, our group have also found out that lacking of HDAC11 result in an increased suppressive activity of the Myeloid-derived Suppressor Cells (MDSCs). The previous publication of our group had shown that the tumor bearing mice experienced a much more aggressive growth pattern in the HDAC11 KO mice compare with C57BL/6 wild type control. MDSCs isolated from mice lacking HDAC11 appeared to gain increased capability to suppress the function of antigen-specific CD8+ T cells in vitro. Followed by this initial study, in chapter 3, we observed an up-regulation of both expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activity of Arg1 and Nos2 in HDAC11KO MDSCs is possibly result from an over-expression of the lineage-specific transcription factor C/EBPβ, which is previously proved to be essential for the differentiation of functional MDSCs. Furthermore, our ChIP data confirmed that HDAC11 may play as an negative regulator of C/EBPβ. Recently, our lab had demonstrated that T cells lacking HDAC11 gained a hyperactive phenotype and anti-tumor effect, indicating that HDAC11 may play a dual role in the host immune system. We further performed an adoptive transfer therapy to C57BL/6 tumor bearing mice. Our data showed that the additional administration of HDAC11KO MDSCs could eliminate, at least partially, the anti-tumor effect by adoptive transfer of HDAC11KO T cells.
Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator in the myeloid cells differentiation and function. Based on our data and previous work from our lab, we propose a dual role of HDAC11 played in the host immune system. In the absence of HDAC11, host defenders such as neutrophils and T cells are functionally more aggressive against intruders such as pathogen and cancer. However, the immune suppressors such as MDSCs became more suppressive. The contradictory role HDAC11 played in the immune system may provide some insights for the assessment of the pharmacological value of HDAC11 and contribute to the development of novel immunotherapeutic strategies.
| Identifer | oai:union.ndltd.org:USF/oai:scholarcommons.usf.edu:etd-8805 |
| Date | 12 January 2018 |
| Creators | Chen, Jie |
| Publisher | Scholar Commons |
| Source Sets | University of South Flordia |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Graduate Theses and Dissertations |
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