Characterization of mouse BATF as a negative regulator of AP-1 activity in vivo
Abstract
Eukaryotic transcription is regulated, in part, through the binding of nuclear proteins to specific DNA sequences within the promoter and enhancer regions of genes. BATF, a member of the AP-1 subfamily of bZIP transcription factors that includes Fos and Jun, forms heterodimers with Jun proteins to bind specifically to AP-1 sites in DNA. In contrast to Fos/Jun heterodimers that act to stimulate gene transcription, BATF/Jun heterodimers are inert and function to inhibit biological processes. BATF mRNA expression is detected predominantly in hematopoietic cells and tissues of humans and mice. In situ hybridization studies of murine thymus tissue indicate that BATF is expressed at discrete stages of T lymphocyte development. Further analysis revealed that BATF is not expressed in double-positive (CD4+ and CD8+) thymocytes, yet is expressed at the more mature single-positive (CD4+ or CD8+) stage. Additionally, BATF is expressed in both naive and Th1 and Th2 CD4+ T cells isolated from the periphery and is upregulated after T cell activation. Transgenic mice that overexpress BATF during T cell development in the thymus and spleen were crossed with AP-1 luciferase reporter mice, and the offspring displayed a significant decrease in AP-1 reporter activity in vivo. The proliferative response of T cells to specific mitogens is decreased in BATF transgenic mice. Further analysis revealed that IL-4, IL-5, IL-10 and IL-13 cytokine expression is downregulated in the thymus of BATF transgenic mice. This pattern of cytokine expression suggests that BATF overexpression is affecting a subset of T cells known as NKT cells, which are thought to be largely responsible for cytokine expression in the thymus. IL-4 and IL-13 expression, which is dependent on functional NKT cells after in vivo anti-CD3ϵ antibody injection, is not induced in the spleens of BATF transgenic mice. PCR analysis for the canonical Vα14Jα281 NKT cell T cell receptor indicates that NKT cell numbers are dramatically reduced in BATF transgenic mice. To date, this is the first evidence that transgenic expression of a negative regulator of the AP-1 family can selectively impair the proper function and development of NKT cells and not the development of other T cell lineages.
Degree
Ph.D.
Advisors
Taparowsky, Purdue University.
Subject Area
Molecular biology|Cellular biology
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