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Thomas Jefferson University - David L Wiest, Ph.D.
David L Wiest, Ph.D.

Microbiology and Immunology
Fox Chase Cancer Center
Immune Cell Development and Host Defense Program
Blood Cell Develoment and Cancer Keystone
Professor
Appointed: 1995

Thomas Jefferson University
Jefferson Medical College
Department of Microbiology and Immunology
Adjunct Associate Professor
Appointed: 2004
Mailing Address
Fox Chase Cancer Center, R390, 333 Cottman Avenue
Philadelphia, Pennsylvania 19111
United States
Contact Information
Phone: 215-728-2966
Fax: 215-728-2412
DL_Wiest@FCCC.edu
Qualifications
Ph.D. Duke University, Immunology, 1991
B.S. Microbiology, Penn. State University, 1984
Expertise and Research Interests
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 alpha-beta or gamma-delta) and subunits that are invariant proteins and serve to transmit signals (CD3gamma, delta, epsilon and zeta). 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 process are corrupted during development of cancer. As indicated above, there are two types of TCR variable proteins, alpha-beta and gamma-delta. Utilization of these alpha-beta and gamma-delta pairs characterizes two distinct types of T lineages, alpha-beta and gamma-delta, 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 fate adoption (i.e., alpha-beta and gamma-delta). We are also interested in identifying the downstream molecular targets of those signals that are essential for development of these two different T cell types. We hypothesize that genes, which are essential for normal cell development, are also likely to regulate development of cancer. Indeed, we have recently identified such a gene, which encodes a component of a cellular machine used to synthesize all cellular proteins. This component, termed Rpl22, is not only essential for normal T cell development, but also may contribute to development of human T cell cancers termed T acute lymphoblastic leukemia (T-ALL).
Keywords
T cell receptor; T cell development; thymus; alpha-beta; gamma-delta; lineage commitment; transformation; translational regulation
Publications
  • 2009

  • Xu, M., Sharma, A., Wiest, D.L., and Sen, J.M. Pre-TCR induced beta-catenin facilitates traversal through beta-selection by regulating expression of Egr Genes. J. Immunol. 182:751-8. (2009) PMC2657338

  • Xu, M., Sharma, A., Houssain, M.Z., Wiest, D.L., and Sen, J.M. Sustained expression of pre-TCR-induced ²-catenin in post beta-selection thymocytes blocks T cell development. J. Immunol. 182:759-65. (2009) PMC2701226

  • Paul, E., Cronan, R., Weston, P.J., Boekelheide, K., Sedivy, J.M., Lee, S.-Y., Wiest, D.L., Resnick, M.B., and Klysik, J.E. Conditional disruption of the mouse Supv3L1 (Suv3) helicase damages the skin, causes psoriasis-like changes, sarcopenia, loss of fat, kyphosis and death. Mammalian Genome 20:92-108. (2009) NIHMS98283

  • Timakhov, R.A., Tan, Y., Rao, M., Liu, Z., Altomare, D.A., Pei, J., Xu, J., Wiest, D.L., Favorova, O.O., Knepper, J.E., and Testa, J.R. Recurrent chromosomal rearrangements implicate oncogenes that contribute to T-cell lymphomagenesis in Akt2 transgenic mice. Genes Chromosomes Cancer 48:786-94. (2009) PMC2739734

  • 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. Marked induction of the helix-loop-helix protein Id3 promotes the gamma-delta T cell fate and renders their functional maturation Notch-independent. Immunity 31: 565-575. (2009) NIHMS150531

  • 2008

  • Tan, Y., Timakhov, R.A., Rao, M., Altomare, D.A., Liu, Z., Gao, Q., Di Cristofano, A., Wiest, D.L., Knepper, J.E., and Testa, J.R. A novel recurrent chromosomal inversion implicates the homeobox bigene pair Dlx5/Dlx6 in T-Cell lymphomas from Lck-Akt2 transgenic mice. Cancer Research 68:1296-1302. (2008)

  • Gururajan, M., Simmons, A., Dasu, T., Spear, B.T., Calulot, C., Robertson, D., Wiest, D.L., Monroe. J., and Bondada, S. Early growth response genes regulate B cell development, proliferation and immune response. J. Immunol 181:4590-4602. (2008) PMC2592513

  • Lauritsen, J.P.H., Kurella, S., Lee, S.Y., Lefebvre, J.M., Rhodes, Gridley, T., Alberola-Ila, J., and Wiest, D.L. Egr2 is required for Bcl-2 induction during positive selection. J. Immunol, 181:7778-7785. (2008) PMC2587029

  • 2007

  • Roberts, J.L., Lauritsen, J,P.H., Cooney, M., Parrott1, R.E., Sajaroff, E.O., Win, C.M., Keller, M.D., Carpenter, J.H., Carbarana, J., Krangel, M.S., Sarzotti, M., Zhong, X.-P., Wiest, D.L., and Buckley, R.H. T-B+NK+ Severe Combined Immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T cell antigen receptor complex. Blood, 109:3198-3206. (2007)

  • Mao, C., Tili-Michaille, E.G., Dose, M., Haks, M.C., Bear, S.E., Maraoulakou, I., Gaitanaris, G.A., Fidanza, V., Ludwig, T., Wiest, D.L., Gounari, F., and Tsichlis, P.N. Unequal contribution of Akt isoforms in the DN to DP thymocyte transition. J. Immunol., 178:5443-5453. (2007)

  • Carter, J.H., Lefebvre, J.M., Wiest, D.L., and Tourtellotte, W.G. Redundant role of early growth response (Egr) transcriptional regulators in thymocyte differentiation and survival. J. Immunol. 178:6796-805. (2007)

  • Schrum, A.G., Gil, D., Dopfer, E.P., Schamel, W.W.A., Wiest, D.L., Turka, L.A., Palmer, E. High-sensitivity detection and quantitative analysis of native protein-protein interactions and multiprotein complexes by flow cytometry. STKE 389:l2. (2007)

  • Anderson, S.J., Lauritsen, J.P., Hartman, M.G., Foushee, A.M., Lefebvre, J.M., Shinton, S.A., Gerhardt, B., Hardy, R.R., Oravecz, T., and Wiest, D.L. Ablation of ribosomal protein L22 selectively impairs alpha-beta T cell development by activation of a p53-dependent checkpoint. Immunity 26:759-772. (2007)

  • Zayed, H., Tolar, J., Xia, L., Yerich, A., Yant, S.R., Kay, M.A., Puttaraju, M., Mansfield, G., Wiest, D.L., McIvor, R.S., Blazar, B.R. Correction of Severe Combined Immune Deficiency (SCID) in multipotent adult progenitor cells (MAPCs) by spliceosome-mediated RNA trans-splicing (SMaRT) using the sleeping beauty transposon delivery system. Molec. Therapy 15:1273-1279. (2007)

  • Koltsova, E.K., Miyazaki, T., Clipstone, N., and Wiest, D.L. 2007. Egr1 and NFATc1 act in concert to promote thymocyte development beyond the beta-selection checkpoint. J. Immunol., 179:4694-4703.

  • Koltsova, E.K., Wiest, D.L., and Vavilova, T.P. Transcription Factors NFAT2 and Egr1 cooperatively regulate the maturation of T-lymphoma in vitro. Biochemistry (Mosc). 72:954-961. (2007)

  • Michie, A.M., Chan, A.C., Ciofani, M., Carleton, M., Lefebvre, J.M., He, Y., Allman, D.M., Wiest, D.L., Zúñiga-Pflücker, J.C., and Izon, D.J. Constitutive Notch signalling promotes CD4+CD8+ thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals. Int. Immunol. 19:1421-1430. (2007)

  • 2006

  • Yamasaki, S., Ishikawa, E., Sakuma, M., Ogata, K., Sakata-Sogawa, K., Hiroshima, M., Wiest, D.L., Tokunaga, M., and Saito, T. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development. Nature Immunology 7:67-75. (2006)

  • Zayed, H., McIvor, R.S., Wiest, D.L., Blazar, B.R. In vitro functional correction of the mutation responsible for murine Severe Combined Immune Deficiency by small fragment homologous replacement. Hum. Gene Ther. 17:158-66. (2006)

  • Ciofani, M. Knowles, G.C., Wiest, D.L., von Boehmer, H., and Zúñiga-Pflücker, J.C. Stage-specific and differential dependency at the alpha/beta-gamma-delta T lineage bifurcation branchpoint. Immunity 25:105-16. (2006)

  • Ke, J., Gururajan, M., Kumar, A., Simmons, A., Turcios, L., Chelvarajan, R.L., Cohen, D.M., Wiest, D.L., Monroe, J.G., and Bondada, S. The role of MAP kinases in BCR induced down-regulation of Egr-1 in immature B lymphoma cells. J. Biol. Chem., 281:39806-18. (2006)

  • 2005

  • Lefebvre, J.M., Haks, M.C., Carleton, M.O., Rhodes, M., Gomathinayagam, T., Su, G.H., Simon, M.C., Eisenlohr, L.C., Garret-Sinha, L., and Wiest, D.L. Enforced expression of Spi-B reverses T lineage commitment and blocks ²-selection. J. Immunol. 174:6184-6194. (2005)

  • Dionne, C.J., Tse, K.Y., Weiss, A.H., Franco, C.B., Wiest, D.L., Anderson, M.K., and Rothenberg, E.V. Subversion of T lineage commitment by PU.1 in a clonal cell line system. Developmental Biology 280:448-466. (2005)

  • Haks, M.C., Lefebvre, J.M., Lauritsen, J.P.H., Carleton, M.O., Rhodes, M., Kappes, D.J., and Wiest, D.L. Attenuation of gamma-delta TCR signaling efficiently diverts thymocytes to the alpha-beta lineage. Immunity 22: 595-606. (2005)

Individual Expertise profile of David L Wiest, Ph.D., Copyright © David L Wiest, Ph.D..
Last Updated by David Wiest, Ph.D. : Wednesday, October 21, 2009 11:04:02 AM



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