This FIRCA application represents a collaboration between Dr. Susan Kaech at Yale University in the US and Dr. Batu Erman at Sabanci University in Istanbul, Turkey.
The Specific Aims stem from those of a parent NIH R01 grant awarded to Dr. Kaech (AI066232) entitled """"""""Regulation of Memory CD8 T cell development."""""""" Effective protection against infectious disease is one of the most critical global health problems facing us today, and will continue to as the world population grows to more than 9 billion. For many developing countries, inadequate control or treatment of infectious disease is the root of most socio- economic problems. The website of the Turkish State Institute of Statistics indicates that in 2004, 4.2% of all hospitalizations and 2.5% of all mortality resulted from infectious or parasitic diseases (www.turkstat.gov.tr). Moreover, most recent statistics from the World Health Organization Statistical Information Systems indicate that the years of life lost to communicable diseases is 44% in Turkey whereas it is 9% for the U.S. (www.who.int/whosis/database). Vaccination offers the greatest hope for reducing the negative impact of infectious disease by generating long-lived immunity, which is based primarily on the formation of memory T and B cells and antibody-secreting plasma cells. Over the past decade, our understanding of how these cells are generated by vaccination and infection has increased at a profound rate, but clearly much remains to be discovered. In particular, this FIRCA proposal focuses on enhancing our basic understanding of naove and memory T cell development and homeostasis via the cytokine interleukin-7 (IL-7). Naove and memory T cell survival relies on their ability to """"""""see"""""""" IL-7 via the IL-7 receptor (IL-7R), and defects in IL-7:IL-7R signaling cause severe immunodeficiency. In addition, generation of long-lived protective memory T cells requires IL-7R signaling and in many chronic viral infections (such as HIV, HCV, EBV) the antiviral T cells often express low levels of IL-7R and this may contribute to their reduced fitness, longevity and ability to stave off the infection. However, little is known about the transcriptional regulation of IL-7R expression on T cells. Here, we propose to characterize the epigenetic regulation of IL-7R and to identify key regulatory regions and specific transcription factors (TFs) that control IL-7R expression during the development of T cells in the thymus and of memory T cells during viral infection in mice. Specifically, we will characterize histone modifications and the binding of three critical TFs (GABP1, Gfi-1 and NF:B) at three evolutionarily conserved regions of Il7ra. Moreover, we will test the requirement of these TFs bound to Il7ra to activate and repress transcription in vivo using an IL-7R:GFP reporter tg system. The long-term goal is to identify the transcription factors that bind to these regions to regulate IL-7R expression. Deeper insight into the molecular mechanism of IL-7R expression could lead to therapies in which IL-7R expression on T cells could be manipulated, and possibly, improve immune function during infection or vaccination.
Effective vaccines against infectious disease, and perhaps, even cancer depend on generating potent T and B cell responses that create long-lived memory T and B cells and IL-7 is an essential survival factor for these cells. The broad goal of this proposal is to understand how T cells regulate the expression of the survival signaling IL-7 receptor (IL-7R) on their cell surfaces in order to properly develop and persist for long periods of time, and here, we propose to test the requirement of specific genomic elements and transcription factor binding sites for proper expression and repression of IL-7R in T cells in vivo during important developmental stages (as they transit from thymocytes`naove`activated`memory T cells) using a novel tool, an IL-7R:GFP reporter transgenic mouse. This work will provide basic information on the mechanisms of T cell survival and homeostasis and could lead to improved vaccines and T cell-oriented therapies that enhance human health worldwide against infectious disease and cancer.
| Ligons, Davinna L; Tuncer, Ceren; Linowes, Brett A et al. (2012) CD8 lineage-specific regulation of interleukin-7 receptor expression by the transcriptional repressor Gfi1. J Biol Chem 287:34386-99 |
