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Philip King, Ph.D.
Associate Professor,
Department of Microbiology and Immunology

Signal Integration in T cells

    Upon encounter with antigen T cells may respond in a number of different ways. In productive immune responses, T cells proliferate and differentiate into mature Th1, Th2 or Th17 cells or killer cells. Alternatively, in responses associated with the maintenance of self tolerance, T cells undergo programmed cell death, enter into a state of prolonged hypo-responsiveness known as anergy, or develop into T regulatory cells. An important determinant that controls the type of T cell response is the nature of additional signals received by T cells at the time of antigenic challenge. These additional signals are derived from co-stimulatory, cytokine or inhibitory receptors which thus integrate (or not) with T cell antigen receptor signals to achieve different functional outcomes.

    Research in our laboratory is aimed at a molecular understanding of mechanisms of signal integration in T cells. To this end we study the role of a variety of intracellular signaling molecules including protein and lipid kinases, phosphatases, adapter proteins and transcription factors as potential signal integrators. In our studies we employ a wide range of biochemical, cell and molecular-biological, and immunological techniques to answer important questions in this area. As well as attempting to elucidate mechanisms of signal integration at the molecular level, the laboratory uses Cre- loxP gene-targeting
technology to explore the relevance of different signaling pathways to
T cell function in whole animals. Furthermore, these approaches have
opened-up new areas of investigation in the laboratory that include
developmental biology, cancer etiology, lymphatic vessel biology and


Selected Publications

Burrows P.E., Gonzalez-Garay M., Rasmussen J.C., Aldrich M.E., Gulloid R., Maus E.A., Fife C.E., Kwon S., Lapinski P.E., King P.D. and Sevick-Muraca E.M. 2013. Lymphatic abnormalities are associated with RASA1 mutations in mouse and man. Proc. Natl. Acad. Sci. USA. 110:8621-8626. 

King P.D., Lubeck B.A. and Lapinski P.E. 2013. Non-redundant functions for Ras-GTPase-activating proteins in tissue homeostasis. Science Signaling
6 (264):1-11.

Lapinski P.E., Kwon S., Lubeck B.A., Wilkinson J.E., Srinivasan, S., Sevick-Muraca E. and King P.D. 2012. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J. Clin. Invest.122: 733-747. 

Lapinski P.E., Qiao Y., Chang C-H. and King P.D. 2011. A role for p120 RasGAP (RASA1) in thymocyte positive selection and survival of naïve T cells in mice.
J. Immunol.

 Bauler T.J., Kamiya N., Lapinski P.E., Langewisch E., Mishina Y., Wilkinson J.E., Feng G.S. and King P.D. 2011. Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations. Dis. Model. Mech. 4:228-239. 

Anand S., Majeti B.K., Acevedo L.M., Murphy E.A., Mukthavaram R.,
Scheppke L., Huang M., Shields D.J., Lindquist J.N., Lapinski P.E.,
King P.D., Weis S.M., and Cheresh D.A. 2010. MicroRNA-132 mediated
loss of p120RasGAP activates quiescent endothelium to facilitate
pathological angiogenesis. Nat. Med. 16:909-914.

Lapinski P.E., Oliver J.A., Bodie J.N., Marti F. and King P.D. 2009.
The T cell-specific adapter protein family: TSAd, ALX and SH2D4A/
SH2D4B. Immunol. Rev. 232:240-254.

Bauler T.J., Hughes E.D., Arimura Y., Mustelin T., Saunders T.L. and King P.D. 2007. Normal TCR signal transduction in mice that lack catalytically-active PTPN3 protein tyrosine phosphatase. J. Immunol. 178:3680-3687.

Marti F., Garcia G., Lapinski P.E., MacGregor J.N. and King P.D. 2006. Essential role of the T cell-specific adapter protein in the activation of the LCK protein tyrosine kinase in peripheral T cells. J. Exp. Med. 203:281-287.

Drappa J., Chan E., Kamen L., Marti F. and King P.D. 2003. Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter (TSAd) protein-deficient mice. J. Exp. Med. 198:809.

Brentjens R., Latouche J-B, Santos E., Marti F., Gong M., Lyddane C., Riviere I. , King P.D. , Weiss M., Larson S. and Sadelain, M. 2003. Eradication of systemic B cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9:279

Marti F., Post N.H. , Chan E. and King P.D. 2001. A transcription function for the T cell-specific adapter (TSAd) protein in T cells: Critical role of the TSAd Src homology 2 domain. J. Exp. Med. 193:1425.

Marti F., Krause A., Post N.H. , Lyddane C., Dupont B., Sadelain M. and King P.D. 2001. Negative-feedback regulation CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6. J. Immunol. 166:197.



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