Littman Laboratory: T Cell Development and Retroviral Pathogenesis

Ivana Djuretic
Harvard Medical School ‘08, Ph.D. Immunology
University of Massachusetts ‘03, B.S. Biochemistry
Hometown: Podgorica, Montenegro
Ivana.djuretic@med.harvard.edu

During my graduate studies, I was interested in identifying transcription factors required for the repression of the Interleukin-4 (Il4) gene during CD4+ T (helper) cell differentiation. This is how we stumbled upon the transcription factor Runx3 that had been described in my current laboratory as a key lineage-specification factor for the development of CD8+ T (cytotoxic) cells in the thymus. We found that Runx3 was induced and bound to the Il4 silencer in activated CD4+ T cells when differentiation was skewed towards the T helper 1 (Th1) pathway, and that Runx3, together with T-bet, repressed Il4 by binding to the Il4 silencer. I have also shown that proteins from the Groucho family of corepressors were recruited to the Il4 silencer in a Runx3-dependent manner, however, the mechanism by which Runx3 and Groucho proteins induce Il4 repression in Th1 cells remains unknown.
Similarly, Dr. Littman’s laboratory had shown that Runx3 bound to the Cd4 silencer in developing CD8+ thymocytes. Runx3-mediated repression of Cd4 in CD8+ T cells is considered to be epigenetic: both Runx3 and the Cd4 silencer become dispensable for maintenance of Cd4 repression in mature CD8+ T cells. Thus, the CD4-CD8 lineage decision in the thymus represents a good model system for studying how epigenetic regulation of gene expression is achieved, and which molecular players are involved in mammalian cells. We are particularly interested in identifying whether noncoding RNA plays a role in this process by cooperating with transcription factors and the chromatin modifying machinery.

Publications

1. Djuretic I, Ansel KM, Leatherbee K, Lei Y, Levanon D, Liu XS, Groner Y & Rao A. Runx3 and the co-repressor Groucho (Grg/Tle) repress gene targets in CD8+ T cells by binding to histone 3 lysine 4 dimethylated sites and inducing histone 3 lysine 27 trimethylation. Submitted.

2. Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, Groner Y, Rao A. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTL. J Exp Med. 2009 Jan 16;206(1):51-9.

3. Hu H, Djuretic I, Sundrud MS, Rao A. Transcriptional partners in regulatory T cells: Foxp3, Runx, and NFAT. Trends Immunol. 2007 Aug;28(8):329-32.

4. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, and Ansel KM. Transcription factors T-bet and Runx3 co-operate to activate IFN-g and repress IL-4. Nat Immunol. 2007 Feb;8(2):145-53.

5. Ansel KM, Djuretic I, Tanasa B, and Rao A. Regulation of Th2 differentiation and the Il4 locus. Annu Rev Immunol 2006; 24: 607-656. Review.

6. Ansel KM, Greenwald RJ, Agarwal S, Bassing CH, Monticelli S, Interlandi J, Djuretic IM, Lee DU, Sharpe AH, Alt FW, and Rao A. Deletion of a conserved silencer impairs T helper type-1 mediated immunity. Nat Immunol 2004; 5: 1251-1259.