David L. Wiest, PhD
Office Phone: 215-728-2966
Lab Phone: 215-728-2968
T lymphocytes recognize and destroy invading pathogens through an assembly of proteins called the T cell antigen receptor (TCR) complex. The TCR has protein subunits that are highly variable and responsible for target recognition (either α/β or γ/δ) and subunits that are invariant proteins and serve to transmit signals (CD3γδε and ζ). This critical protein assembly (the TCR) controls not only the behavior of mature T lymphocytes but also their development in the thymus. My laboratory seeks to understand how T cell development is controlled by the TCR and how these developmental processes are corrupted during development of cancer. There are two types of TCR variable proteins, α/β and γ/δ. Utilization of these α/β and γ/δ pairs characterizes two distinct types of T lineages, α/β and γ/δ, respectively. These two T lineages are thought to arise from a single immature precursor in the thymus. We are attempting to identify the cellular factors that are essential for transmitting the signals that direct adoption of these alternate fates (i.e., αβ or γδ). We hypothesize that the genes, which are essential for normal cell development, are also likely to regulate development of cancer. Indeed, through these efforts we have identified such a factor, Rpl22, which is a component of the cellular machine responsible for synthesis of all cellular proteins, the ribosome. Rpl22, is not only essential for normal T cell development, but also may regulate the development of human cancers including T acute lymphoblastic leukemia (T-ALL), myelodysplastic syndromes (MDS), and acute myelogenous leukemia (AML).Description of research projects
Fox Chase Programs
- Coffey, F., Lee, S.-Y., Buus, T.B., Lauritsen, J.-P.H., Wong, G.W., Zúñiga-Pflücker, J.C., Kappes, D.J., and Wiest, D.L. 2014. The TCR ligand-inducible expression of CD73 marks γδ lineage commitment and a metastable intermediate in effector specification. J. Exp. Med. 211:329-43. PMC3920555.
- Zhang, Y., Duc, A.-C.E., Rao, S., Sun, X.-L., Bilbee, A.N., Rhodes, M., Li, Q., Kappes, D.J., Rhodes, J., and Wiest, D.L., 2013. Control of hematopoietic stem cell emergence by antagonistic functions of ribosomal protein paralogs. Dev. Cell 24:411-425. NIHMS440478
- Rao, S., Lee, S.Y., Gutierrez, A., Perrigoue, J., Thapa, R.J., Tu, Z., Jeffers, J.R., Rhodes, M., Anderson, S., Oravecz, T., Hunger, S.P., Timakhov, R.A., Zhang, R., Balachandran, S., Zambetti, G., Testa, J.R., Look, A.T., and Coffey, F., Lee, S.-Y., Buus, T.B., Lauritsen, J.-P.H., Wong, G.W., Zúñiga-Pflücker, J.C., Kappes, D.J., and Wiest, D.L. 2012. Inactivation of the ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood 120:3764-3773. PMC3488889
- Roberts, J.L., Buckley, R.H., Liu, B., Pei, J., Lapidus, A., Peri, S., Wei, Q., Shin, J.,. Parrott, R.E., Dunbrack, R., Testa, J.R., Zhong, X.-P., and Wiest, D.L. 2012. CD45 deficient severe combined immunodeficiency caused by uniparental disomy. PNAS 109:10456-10461. PMC3387083
- Lauritsen, J.P.H., Wong, G.W., Lee, S.Y., Lefebvre, J.M., Ciofani, M., Rhodes, M., Kappes, D.J., Zúñiga-Pflücker, J.C., and Wiest, D.L. 2009. Marked induction of the helix-loop-helix protein Id3 promotes the γδ T cell fate and renders their functional maturation Notch-independent. Immunity 31: 565-575. PMC2768560 2012.