Philip D. King
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.
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 naive T cells in mice. J. Immunol. 187:151-163.
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.