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Faculty > Faculty Alphabetical > Kenneth Murphy, MD, PhD

Eugene 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. Nave 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 - PresentLead AuthorJaneway's Immunobiology, Garland Science
2001 - PresentTransmitting EditorInternational Immunology
2001 - PresentEditorial BoardEuropean Journal of Immunology
2000 - PresentAssociate EditorImmunity
1997 - 2000EditorImmunity

Service to the Department

2009 - PresentSelection Committee for Faculty Affairs
2008 - PresentCell Biology Search Committee
2008 - PresentSpeaker Committee, Pathology and Immunology
2008 - PresentDBBS Evaluation Committee, Pathology and Immunology
2000 - 2007Barnes Hospital Medical Staff, Department of Pathology
2000 - PresentImmunology Student Admissions Committee
1997 - 2000American Association of Immunologist Nominating Committee
1992 - PresentSteering Committee, Immunology Program
1992 - PresentDBBS Admissions Committee
1992 - 1995Graduate School Admissions Committee

Service to the University

1997 - PresentInvestigator, Howard Hughes Medical Institute

DBBS Graduate Program Affiliation

Immunology Program
Developmental Biology Program

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
    Jrn 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