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Faculty > Faculty Alphabetical > Kenneth Murphy, MD, PhDProfessor, Pathology and Immunology
Investigator, Howard Hughes Medical Institute
Room 7766, CSRB
Office: (314) 362-2009
Lab: (314) 362-2004
E-mail: kmurphy@wustl.edu
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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
| | 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
| | 2000 - Present | Barnes Hospital Medical Staff, Department of Pathology | | 2000 - Present | Immunology Student Admissions Committee | | 1992 - 1995 | Graduate School Admissions Committee |
Service to the University
| | Present | Investigator, Howard Hughes Institute |
Clinical Interest
| | Anatomic and Molecular Pathology - Autopsy Pathology |
Selected Publications
| | Weaver CT, Murphy KM. T-cell subsets: the more the merrier.. Current Biology 23:17(2):R61-3, 2007 Abstract
| | Gavrieli M, Sedy J, Nelson CA, Murphy KM. BTLA and HVEM cross talk regulates inhibition and costimulation.. Adv. Immunology 92:157-85, 2006 Abstract
| | Murphy KM. Stress management for T helper differentiation. Nature Immunology 7, 553-555, 2006 Abstract
| | Lindsley RC, Gill JG, Kyba M, Murphy TL, Murphy KM.. Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm.. Development 133(19):3787-96, 2006 Abstract
| | Murphy KM, Nelson CA, Sedy JR. Balancing co-stimulation and inhibition with BTLA and HVEM. Nature Reviews Immunology 6(9):671-81, 2006 Abstract
| | Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. Interleukin 17-producing CD4(+) effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunology 6:1123-1132, 2005 Abstract
| | Chen C, Ouyang W, Grigura V, Zhou Q, Carnes K, Lim H, Zhao GQ, Arber S, Kurpios N, Murphy TL, Cheng AM, Hassell JA, Chandrashekar V, Hofmann MC, Hess RA, Murphy KM. ERM is required for transcriptional control of the spermatogonial stem cell niche.. Nature 18;436(7053):1030-4, 2005 Abstract
| | Ota N, Brett TJ, Murphy TL, Fremont DH, Murphy KM.. N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation.. Nature Immunology 5(2):208-15, 2004 Abstract
| | Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL, Murphy KM. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nature Immunology 6(1):90-8, 2004 Abstract
| | Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, Murphy KM.. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.. Nature Immunology 4(7):670-9, 2003 Abstract
| | Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM. IL-18-stimulated GADD45b required in cytokine-induced, but not TCR-induced, IFN-ã production. Nature Immunology 2:157-164, 2001 Abstract
| | Ranganath SR, Murphy KM. Structure and specificity of GATA proteins in Th2 development. Mol Cell Biol 21:2716-2725, 2001 Abstract
| | Asnagli H, Murphy KM. Stability and commitment in T helper development. [Review] In: Curr Opin Immunol 13:242-247, 2001 Abstract
| | Farrar JD, Smith JD, Murphy TL, Leung S, Stark GR, Murphy KM. Selective loss of Type 1 interferon-induced Stat4 activation caused by a minisatellite insertion in mouse Stat2. Nature Immunology 1:65-69, 2000 Abstract
| | Farrar JD, Smith JD, Murphy T., Murphy KM. Recruitment of Stat4 to the human IFN-á/â receptor requires activated Stat2. J Biol Chem 275:2693-2697, 2000 Abstract
| | Glimcher LH, Murphy KM. Lineage commitment in the immune system: the T helper lymphocyte grows up. [Review] In: Genes & Dev 14:1693-1711, 2000 Abstract
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Current Trainees
| | Jennifer Gibson Gill, PhD | | Barbara Schraml, B.S. | | Peter Wilker, PhD | | Brian Edelson, MD, PhD | | Maya Gavrieli, PhD | | Kai Hildner, MD, PhD | | Wataru Ise, PhD | | Masako Kohyama Ise, PhD | | Michelle Sandau, PhD |
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