Kenneth Murphy, MD, PhD

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

Research

Cellular Overdrive:  regulation of T cell-mediated immunity by dendritic cells.

Since I started my laboratory, we have studied cell-mediated immunity, beginning with discovering the link between IL-12 and T helper 1 development.  Cell-mediated immunity - meaning the induction of robust CD8 and CD4 T cell responses, as opposed to antibody generation - underlies effective responses against intracellular pathogens, including viruses such as HIV and intracellular bacteria such as Mycobacteria tuberculosis.  The greatest challenge facing immunology is the development of vaccines that drive effective and durable cell-mediated responses.  The failure of current vaccines to do this leaves a huge gap in our ability to effectively prevent and treat some of the world's most threatening infections.  We aim to understand cell-mediated immunity and leverage this knowledge to design effective treatments for intracellular pathogens and cancer vaccines. 

Our analysis of cell-mediated immunity takes two approaches, examining both the development and the specific effector mechanisms of the cells involved.  Within CD4+ T cells, the cells destroyed by HIV in AIDS, developmental choices control the naïve CD4+ T cells emergence into distinct effector lineages, such as the Th1, Th17, or Th2 subsets.  We pioneered the use of TCR-transgenic mice to study T cell differentiation of these subsets.  We defined many of signals that direct these choices, including the effects of cytokines like IL-12 and IL-4, the role of JAK/STAT pathway, and several transcription factors such as STAT4 and GATA3 involved in these pathways.  Recently, we identified the novel transcription factor Batf, which controls both Th17 development by regulating RORt and IL-17 directly, and T follicular helper development by regulating cMaf and Bcl6, the so-called 'master' regulators of this subset.

Within dendritic cells (DCs), developmental choices also are critical for controlling cell-mediated immunity.  DCs are comprised of several distinct lineages that have differing functions.  One subset, the "CD8+ classical DC", is critical for the activation of CD8 T cells during infections by many viruses.  The capacity of this cell to "cross-prime" T cells - meaning the presentation of exogenous antigens on MHC class I to CD8 T cells leading to their activation – is a unique and specialized feature of this subset of dendritic cells.  We discovered that the transcription factor Batf3 is specifically in control of development of CD8+ cDCs, and that mice lacking Batf3 fail to respond to many viruses.  This area is a major focus in the lab currently, and our aim is to study the development of this DC subset further to understand why it is normally held to very low numbers within the population of DCs in the body, and perhaps to develop strategies that will increase their numbers and augment their effectiveness in driving responses to synthetic vaccines.  Recent findings in the lab have uncovered alternative pathways of its development that suggest that these aims might be achievable. 

Selected Publications

  1. Hsieh, C. S., S. E. Macatonia, C. S. Tripp, S. F. Wolf, A. O'Garra, and K. M. Murphy. 1993. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547-549. PM:809733
  2. Guler, M. L., J. D. Gorham, C. S. Hsieh, A. J. Mackey, R. G. Steen, W. F. Dietrich, and K. M. Murphy. 1996. Genetic susceptibility to Leishmania: IL-12 responsiveness in TH1 cell development. Science 271:984-987. PM:8584935
  3. 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. 2008. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322:1097-1100. PM:19008445
  4. 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. 2008. Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs. Cell Stem Cell 3:55-68. PM:18593559
  5. Kohyama, M., W. Ise, B. T. Edelson, P. R. Wilker, K. Hildner, C. Mejia, W. A. Frazier, T. L. Murphy, and K. M. Murphy. 2009. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457:318-321. PM:19037245
  6. O'Garra, A. and K. M. Murphy. 2009. From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce T(H)1 development. Nature Immunol 10:929-932. PM:19692989
  7. 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. 2009. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460:405-409. PM:19578362
  8. 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. 2010. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8{alpha}+ conventional dendritic cells.  J Exp.Med. PM:20351058
  9. Ise, W., M. Kohyama, K. M. Nutsch, H. M. Lee, A. Suri, E. R. Unanue, T. L. Murphy, and K. M. Murphy. 2010. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nature Immunol 11:129-135. PM:20037585
  10. Murphy, K. M. and B. Stockinger. 2010. Effector T cell plasticity: flexibility in the face of changing circumstances. Nature Immunol 11:674-680. PM:20644573
  11. Murphy, T. L. and K. M. Murphy. 2010. Slow Down and Survive: Enigmatic Immunoregulation by BTLA and HVEM. Annu.Rev Immunol 28:389-411. PM:20307212
  12. Gill, J. G., E. M. Langer, R. C. Lindsley, M. Cai, T. L. Murphy, M. Kyba, and K. M. Murphy. 2011. 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. PM:21394833
  13. Ise, W., M. Kohyama, B. U. Schraml, T. Zhang, B. Schwer, U. Basu, F. W. Alt, J. Tang, E. M. Oltz, T. L. Murphy, and K. M. Murphy. 2011. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nature Immunol 12:536-543. PM:21572431
  14. Cai, M., E. M. Langer, J. G. Gill, A. T. Satpathy, J. C. Albring, W. Kc, T. L. Murphy, and K. M. Murphy. 2012. Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation. Blood. PM:22665933
  15. Satpathy, A. T., W. Kc, J. C. Albring, B. T. Edelson, N. M. Kretzer, D. Bhattacharya, T. L. Murphy, and K. M. Murphy. 2012. Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. J.Exp.Med. 209:1135-1152. PM:22615127

DBBS Graduate Program Affiliation

Department of Pathology and Immunology
Campus Box 8118
660 South Euclid Ave.
St. Louis, MO 63110
 
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