Director, Transgenic Mouse Facility
Professor, Blood Cell Development and Function Program
Regulation of T lymphocyte development, CD4/CD8 lineage commitment and oncogenesis.
My laboratory focuses on understanding the molecular basis of T lymphocyte differentiation and function. In particular, we have employed forward and reverse genetic approaches to elucidate the signaling and transcriptional pathways that regulate these processes. In the course of this work, we have generated numerous new transgenic and knockout mouse models, most recently to assess the specific and redundant roles of ThPOK as a key regulator of T cell development, and to dissect its expression pattern and transcriptional control mechanisms in vivo. We have also initiated work in the zebrafish model, in order to exploit the advantages of this system for genetic screens to identify novel regulators of T cell development and lymphomagenesis. Thus, we have generated new CD4 and ThPOK reporter fish, as well as ThPOK knockout fish, which will both greatly facilitate the study of T helper development and function in zebrafish, and provide the basis for their efficient genetic dissection. Finally, we have discovered a new and so far unrecognized role of ThPOK as an oncogene, using novel animal models that we have generated. This work suggests a widespread and important role of ThPOK in diverse human cancers, and has become a major new focus of my lab. Our work in elucidating the process of CD4/CD8 lineage choice and identifying the key role of ThPOK represents a unique and widely recognized contribution to the field. These findings have important implications for therapeutic manipulation of the cell-based immune system including potentially for cancer treatment
Fahl SP, Coffey F, Kain L, Zarin P, Dunbrack RL, Jr., Teyton L, Zuniga-Pflucker JC, Kappes DJ, Wiest DL. Role of a selecting ligand in shaping the murine gammadelta-TCR repertoire. Proceedings of the National Academy of Sciences of the United States of America, 115(8):1889-94, 2018. PMC5828614
Fahl SP, Coffey F, Kain L, Zarin P, Dunbrack RL, Jr., Teyton L, Zuniga-Pflucker JC, Kappes DJ, Wiest DL. Role of a selecting ligand in shaping the murine gammadelta-TCR repertoire. Proc Natl Acad Sci U S A, 115(8):1889-94, 2018. PMC5828614
Kappes, D.J., Tonegawa, S. Surface expression of alternative forms of the TCR/CD3 complex. Proc. Natl. Acad. Sci. USA 88: 10619-10623, 1991. PubMed
Davé, V.P., Cao, Z.-S., Browne, C., Alarcón, B., Fernandez-Miguel, G., Lafaille, J., de la Hera, A., Tonegawa, S., Kappes, D.J. CD3δ deficiency arrests development of the αβ but not the γδ T cell lineage. EMBO J. 16: 1360-1370, 1997. PubMed
Delgado, P., Fernández, E., Davé, V., Kappes, D.J., Alarcón, B. CD3δ couples T-cell receptor signalling to ERK activation and thymocyte positive selection. Nature 406:426-430, 2000. PubMed
Davé, V.P., Allman, D., Keefe, R., Hardy, R.R., Kappes, D.J. HD mice: a novel mouse mutant with a specific defect in the generation of CD4+ T cells. Proc. Natl. Acad. Sci. U.S.A. 95:8187-8192, 1998. PubMed
Keefe, R., Davé, V.P., Allman, D., Wiest, D., Kappes, D.J. Regulation of lineage commitment distinct from positive selection. Science 286:1149-1153, 1999. PubMed
He, Xiao, He, Xi, Davé, V.P., Zhang, Y., Hua, X., Xu, W., Roe, B.A., Kappes, D.J. The zinc finger transcription factor TH POK regulates CD4 versus CD8 T lineage commitment. Nature 433:826-833, 2005. PubMed
Haks, M.C., Lebebvre, J.M., Lauritsen, J.P., Carleton, M., Rhodes, M., Miyazaki, T., Kappes, D.J.*, Wiest, D.L.* Attenuation of γδ TCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22:595-606, 2005. *Denotes authors contributed equally. PubMed
He, X., Park, K., Wang, H., Zhang, Y., Hua, X., Li, Y., Kappes, D.J. CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity 28:346-358, 2008. Accepted prior to April 7, 2008. PubMed
Engel, I., Hammond, K., Sullivan, B.A., He, X., Taniuchi, I., Kappes, D., Kronenberg, M. Co-receptor choice by V alpha14i NKT cells is driven by Th POK expression rather than avoidance of CD8-mediated negative selection. J. Exp. Med. 207:1015-1029, 2010. PMCID: PMC2867285 PubMed
Park, K., He, X., Lee, H. O., Hua, X., Li, Y., Wiest, D., Kappes, D.J. TCR-mediated ThPOK induction promotes development of mature (CD24-) γδ thymocytes. EMBO J. 29:2329-2341, 2010. PMCID: PMC2910264 PubMed
Lee, H.-O., He, X., Mookerjee-Basu, J., Zhongping, D., Hua, X., Nicolas, E., Sulis, M.L., Ferrando, A.A., Testa, J.R., Kappes, D.J. Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 112: 7773-7778, published ahead of print June 8, 2015, doi:10.1073/pnas.1424104112. PMID: 26056302 PubMed
Dietmar.Kappes@fccc.edu
Office Phone: 215-728-5374
Room: R292
Dietmar.Kappes@fccc.edu
Office Phone: 215-728-5374
Room: R292
Director, Transgenic Mouse Facility
Professor, Blood Cell Development and Function Program
Regulation of T lymphocyte development, CD4/CD8 lineage commitment and oncogenesis.
My laboratory focuses on understanding the molecular basis of T lymphocyte differentiation and function. In particular, we have employed forward and reverse genetic approaches to elucidate the signaling and transcriptional pathways that regulate these processes. In the course of this work, we have generated numerous new transgenic and knockout mouse models, most recently to assess the specific and redundant roles of ThPOK as a key regulator of T cell development, and to dissect its expression pattern and transcriptional control mechanisms in vivo. We have also initiated work in the zebrafish model, in order to exploit the advantages of this system for genetic screens to identify novel regulators of T cell development and lymphomagenesis. Thus, we have generated new CD4 and ThPOK reporter fish, as well as ThPOK knockout fish, which will both greatly facilitate the study of T helper development and function in zebrafish, and provide the basis for their efficient genetic dissection. Finally, we have discovered a new and so far unrecognized role of ThPOK as an oncogene, using novel animal models that we have generated. This work suggests a widespread and important role of ThPOK in diverse human cancers, and has become a major new focus of my lab. Our work in elucidating the process of CD4/CD8 lineage choice and identifying the key role of ThPOK represents a unique and widely recognized contribution to the field. These findings have important implications for therapeutic manipulation of the cell-based immune system including potentially for cancer treatment
Fahl SP, Coffey F, Kain L, Zarin P, Dunbrack RL, Jr., Teyton L, Zuniga-Pflucker JC, Kappes DJ, Wiest DL. Role of a selecting ligand in shaping the murine gammadelta-TCR repertoire. Proceedings of the National Academy of Sciences of the United States of America, 115(8):1889-94, 2018. PMC5828614
Fahl SP, Coffey F, Kain L, Zarin P, Dunbrack RL, Jr., Teyton L, Zuniga-Pflucker JC, Kappes DJ, Wiest DL. Role of a selecting ligand in shaping the murine gammadelta-TCR repertoire. Proc Natl Acad Sci U S A, 115(8):1889-94, 2018. PMC5828614
Kappes, D.J., Tonegawa, S. Surface expression of alternative forms of the TCR/CD3 complex. Proc. Natl. Acad. Sci. USA 88: 10619-10623, 1991. PubMed
Davé, V.P., Cao, Z.-S., Browne, C., Alarcón, B., Fernandez-Miguel, G., Lafaille, J., de la Hera, A., Tonegawa, S., Kappes, D.J. CD3δ deficiency arrests development of the αβ but not the γδ T cell lineage. EMBO J. 16: 1360-1370, 1997. PubMed
Delgado, P., Fernández, E., Davé, V., Kappes, D.J., Alarcón, B. CD3δ couples T-cell receptor signalling to ERK activation and thymocyte positive selection. Nature 406:426-430, 2000. PubMed
Davé, V.P., Allman, D., Keefe, R., Hardy, R.R., Kappes, D.J. HD mice: a novel mouse mutant with a specific defect in the generation of CD4+ T cells. Proc. Natl. Acad. Sci. U.S.A. 95:8187-8192, 1998. PubMed
Keefe, R., Davé, V.P., Allman, D., Wiest, D., Kappes, D.J. Regulation of lineage commitment distinct from positive selection. Science 286:1149-1153, 1999. PubMed
He, Xiao, He, Xi, Davé, V.P., Zhang, Y., Hua, X., Xu, W., Roe, B.A., Kappes, D.J. The zinc finger transcription factor TH POK regulates CD4 versus CD8 T lineage commitment. Nature 433:826-833, 2005. PubMed
Haks, M.C., Lebebvre, J.M., Lauritsen, J.P., Carleton, M., Rhodes, M., Miyazaki, T., Kappes, D.J.*, Wiest, D.L.* Attenuation of γδ TCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22:595-606, 2005. *Denotes authors contributed equally. PubMed
He, X., Park, K., Wang, H., Zhang, Y., Hua, X., Li, Y., Kappes, D.J. CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity 28:346-358, 2008. Accepted prior to April 7, 2008. PubMed
Engel, I., Hammond, K., Sullivan, B.A., He, X., Taniuchi, I., Kappes, D., Kronenberg, M. Co-receptor choice by V alpha14i NKT cells is driven by Th POK expression rather than avoidance of CD8-mediated negative selection. J. Exp. Med. 207:1015-1029, 2010. PMCID: PMC2867285 PubMed
Park, K., He, X., Lee, H. O., Hua, X., Li, Y., Wiest, D., Kappes, D.J. TCR-mediated ThPOK induction promotes development of mature (CD24-) γδ thymocytes. EMBO J. 29:2329-2341, 2010. PMCID: PMC2910264 PubMed
Lee, H.-O., He, X., Mookerjee-Basu, J., Zhongping, D., Hua, X., Nicolas, E., Sulis, M.L., Ferrando, A.A., Testa, J.R., Kappes, D.J. Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 112: 7773-7778, published ahead of print June 8, 2015, doi:10.1073/pnas.1424104112. PMID: 26056302 PubMed
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
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