Faculty

	Philip D. King Associate Professor Ph.D., University College London 1991
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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. Studies are expected to reveal novel means by which T cell responses can be manipulated in different pathologic situations including cancer, autoimmunity and infectious disease.

Selected Publications:

    Lapinski P.E., Bauler T.J., Hughes E.D., Saunders T.L., Brown E. and King P.D. 2007. Generation of a conditional allele of the Ras GTPase-Activating Protein (RasGAP) in mice. Genesis. 45:762-767.

    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.

Lapinski P.E., MacGregor J.N., Marti F. and King P.D. 2006. The T cell-specific adapter protein functions as regulator of peripheral but not central immunological tolerance. Adv. Exp. Med. Biol. 584:73-88.

Marti F., Lapinski P.E and King P.D. 2005. Sh2d2a. AfCS-Nature Molecule Pages. (doi:10.1038/mp.a002075.01).

Blank M.C., Masuda E., Marti F., King P.D., Redecha P.B., Wurzburger R.J., Peterson M.G.E., Tanaka S. and Pricop L. 2005. Altered transcription of the human FcgRIIB gene mediated by a promoter polymorphism and association with systemic lupus erythematosus. Hum. Gen. 117:220-227.

Marti F., Lapinski P.E. and King P.D. 2005. The emerging role of the T cell-specific adapter (TSAd) protein as an autoimmune disease-regulator in mouse and man. Immunology Lett. 97:165-170.

Marti F. and King P.D. 2005. The p95-100 kDa ligand of the T cell-specific adapter (TSAd) protein Src-homology-2 (SH2) domain implicated in TSAd nuclear import is p97 Valosin-containing protein (VCP). Immunology Lett. 97:235-243.

King P.D. 2004. Lupus-like autoimmunity caused by defects in T cell signal transduction. Current Opinion in Investigational Drugs. 5:517-523.

Bai L., Yoon S.O., King P.D. and Merchant J.L. 2004. ZBP-89-induced apoptosis is p53-independent and requires JNK. Cell Death Differ. 11:663-673.

Drappa J., Kamen L.A., Chan E., Georgiev M., Ashany D., Marti F. and King P.D. 2003. Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice. J. Exp. Med. 198:809-821.

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. 9:279-286.

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 SH2 domain. J. Exp. Med. 193:425-430.

Marti F., Krause A., Post N.H., Lyddane C., Dupont B., Sadelain M. and King P.D. 2001. Negative-feedback regulation of CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6. J. Immunol. 166:197-206.