         | |
Faculty > Faculty Alphabetical > Kenneth Murphy, MD, PhDEugene Opie First Centennial Professor, Pathology and Immunology
Investigator, Howard Hughes Medical Institute
Room 7766, CSRB
Office: (314) 362-2009
Lab: (314) 362-2004
E-mail: kmurphy ate wustl dot edu
Publication List |  |
Research
| | T cell development, lineage commitment
The major theme of my laboratory is the study of lineage commitment programs. The majority of our work has focused on lineage choices within the immune system, with special interest in T cell development. In addition, our laboratory is interested in early fate choices during embryonic development, such as the mechanisms that generate mesoderm, from which the entire immune system is derived.
The immune system makes many lineage choices. One important choice is made by CD4+ T cells, the cells destroyed by HIV in AIDS. Naïve CD4+ T cells choose between several lineages during an immune response to pathogens, generating different effector subsets. These include subsets named Th1, Th17, Th2 and various regulatory subsets. We pioneered the use of TCR-transgenic mouse to study such T cell differentiation in vitro. With this system, we defined important signals that direct these choices, such as the cytokines IL-12 and IL-4 that act by the JAK/STAT pathway to initiate the Th1 or Th2 programs. We identified many transcriptional steps in Th1 and Th2 differentiation, such as STAT1 induction of T-bet, which induces expression of the IL-12 receptor, allowing for IL-12 activation of STAT4 and subsequent Th1 expansion and effector activity. Current projects in T cell development include analysis of several knockout mice for several new transcription factors that are expressed in a highly polarized manner in T cell subsets.
Work in this area led to the discovery of several novel molecules. We cloned the B and T lymphocyte attenuator (BTLA), a novel receptor expressed by T and B cells. We made BTLA knockout mice to study its role in the immune response, and found increased T cell responses, indicating an inhibitory role for BTLA, and have examined aspects of its signaling, which includes recruitment of inhibitory phosphatases such as SHP-2. Polymorphisms in human BTLA have now been associated with susceptibility to diseases such as Rheumatoid arthritis. A highly unexpected finding came from our search for the natural BTLA ligand. The BTLA ligand was not a member of the B7 immunoglobulin superfamily, as expected, but was a member of the TNF receptor superfamily, Herepesvirus entry mediator (HVEM). This finding represents the first example of an immunoglobulin (Ig) domain receptor interacting with a receptor from the TNFR family.
New projects include other lineage decisions. In the immune system, we study the development of myeloid cells into neutrophils, macrophages, and dendritic cells (DCs). We have identified several novel transcription factors that expressed in discrete myeloid subsets and are now examining their role in vivo using knockout mice. We are interested in the choice made by precursors that distinguishes macrophages from DCs in particular, since DCs are critical to directing the differentiation of CD4 T cells. Finally, a newer project uses embryonic stem (ES) cells to dissect the transcriptional basis of mesoderm development. Our early studies in this area identified the Wnt signaling pathway as critical for inducing the transcription factors that drive development of specific subsets of mesoderm, and we have identified several transcription factors that regulate the development of early mesoderm lineages, such as early components the cardiovascular system. |
Editorial Responsibilities
| | 2005 - Present | Lead Author | Janeway's Immunobiology, Garland Science | | 2001 - Present | Transmitting Editor | International Immunology | | 2001 - Present | Editorial Board | European Journal of Immunology | | 2000 - Present | Associate Editor | Immunity | | 1997 - 2000 | Editor | Immunity |
Service to the Department
| | 2009 - Present | Selection Committee for Faculty Affairs | | 2008 - Present | Cell Biology Search Committee | | 2008 - Present | Speaker Committee, Pathology and Immunology | | 2008 - Present | DBBS Evaluation Committee, Pathology and Immunology | | 2000 - 2007 | Barnes Hospital Medical Staff, Department of Pathology | | 2000 - Present | Immunology Student Admissions Committee | | 1997 - 2000 | American Association of Immunologist Nominating Committee | | 1992 - Present | Steering Committee, Immunology Program | | 1992 - Present | DBBS Admissions Committee | | 1992 - 1995 | Graduate School Admissions Committee |
Service to the University
| | 1997 - Present | Investigator, Howard Hughes Medical Institute |
Clinical Interest
| | Anatomic and Molecular Pathology - Autopsy Pathology |
Selected Publications
| | Gill,J.G., Langer,E.M., Lindsley,R.C., Cai,M., Murphy,T.L., Kyba,M., and Murphy,K.M.. Snail and the microRNA-200 Family Act in Opposition to Regulate Epithelial-to-Mesenchymal Transition and Germ Layer Fate Restriction in Differentiating ESCs. Stem Cells 29:764-776, 2011 Abstract
| | Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, Murphy KM. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol 12:536-543, 2011 Abstract
| | Edelson, B. T., W. Kc, R. Juang, M. Kohyama, L. A. Benoit, P. A. Klekotka, C. Moon, J. C. Albring, W. Ise, D. G. Michael, D. Bhattacharya, T. S. Stappenbeck, M. J. Holtzman, S. S. Sung, T. L. Murphy, K. Hildner, and K. M. Murphy. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8{alpha}+ conventional dendritic cells. J Exp.Med, 2010 Abstract
| | Ise, W., M. Kohyama, K. M. Nutsch, H. M. Lee, A. Suri, E. R. Unanue, T. L. Murphy, and K. M. Murphy. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 11:129-135, 2010 Abstract
| | Kohyama, M., W. Ise, B. T. Edelson, P. R. Wilker, K. Hildner, C. Mejia, W. A. Frazier, T. L. Murphy, and K. M. Murphy. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457:318-321, 2009 Abstract
| | O'Garra, A. and K. M. Murphy. From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce T(H)1 development. Nat Immunol 10:929-932, 2009 Abstract
| | Schraml, B. U., K. Hildner, W. Ise, W. L. Lee, W. A. Smith, B. Solomon, G. Sahota, J. Sim, R. Mukasa, S. Cemerski, R. D. Hatton, G. D. Stormo, C. T. Weaver, J. H. Russell, T. L. Murphy, and K. M. Murphy. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460:405-409, 2009 Abstract
| | Hildner, K., B. T. Edelson, W. E. Purtha, M. Diamond, H. Matsushita, M. Kohyama, B. Calderon, B. U. Schraml, E. R. Unanue, M. S. Diamond, R. D. Schreiber, T. L. Murphy, and K. M. Murphy. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322:1097-1100, 2008 Abstract
| | Lindsley, R. C., J. G. Gill, T. L. Murphy, E. M. Langer, M. Cai, M. Mashayekhi, W. Wang, N. Niwa, J. M. Nerbonne, M. Kyba, and K. M. Murphy. Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs. Cell Stem Cell 3:55-68, 2008 Abstract
| | Guler, M. L., J. D. Gorham, C. S. Hsieh, A. J. Mackey, R. G. Steen, W. F. Dietrich, and K. M. Murphy. Genetic susceptibility to Leishmania: IL-12 responsiveness in TH1 cell development. Science 271:984-987, 1996 Abstract
| | Hsieh, C. S., S. E. Macatonia, C. S. Tripp, S. F. Wolf, A. O'Garra, and K. M. Murphy. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547-549, 1993 Abstract
|
Current Trainees
Graduate Students
Mi Cai, PhD
KC Wumesh, MD, PhD
Nicole Kretzer, MD, PhD
Winnie Lee, PhD
Ansu Satpathy, MD, PhD
Postdoctoral Fellows
Jörn Albring, MD, PhD
Roxane Tussiwand, PhD
Assistant Professor
Brian Edelson, MD, PhD
CP Resident
Malay Haldar
| Past Trainees
Graduate Students
Mona Mashayekhi, MD, PhD
Jennifer Gill, MD, PhD
Barbara Schraml, PhD
Michelle Hurchla, PhD
Peter Wilker, PhD
Robert Lindsley, MD, PhD
Mehmet Guler
Chyi-Song Hsieh
Nils Jacobson
Piotr Kulesza
Wenjun Ouyang
Sheila H. Ranganath
Susanne J. Szabo
Cynthia Wenner
Jianfei Yang
Mei-xia Zhou
Maryam Afkarian
Lisa Berenson, PhD
Chen Chen
Associate Professors
James Gorham, MD, PhD
Postdoctoral Fellows
Maya Gavrieli, PhD
Kai Hildner, M.D., PhD
Wataru Ise, PhD
Masako Kohyama Ise, PhD
Michelle Sandau, PhD
John David Farrar
James Gorham
Shin-ichiro Kagami, MD
Norihiko Watanabe
Jianfei Yang
HeLene Asnagli
Larua L. Carter
Jae Youl Cho
Marc Cleveland
|
|
| |  |
|
