Postdoctoral training, Laboratory of Molecular Oncology, The Rockefeller University, New York (with Dr. Hidesaburo Hanafusa)

Ph.D., Immunology, Cornell University (with Dr. Bo Dupont)

B.S., Medical Technology, California State University , Los Angeles

Avery August - Center for Molecular Immunology & Infectious Disease & Dept. of Veterinary Science

Chavez Carter – Alcorn State :Penn State Bridges Scholar

Maria Diaz - Undergraduate Student

Ayesha Fraser - Undergraduate Student

Elizabeth Hicks - Undergraduate Student

Jianfang Hu – Immunology & Infectious Disease Graduate Student

Archana Iyer - Immunology & Infectious Disease Graduate Student

Margaret Kensinger - Research Technician

Jin Ki Kim - Undergraduate Student

Man Kit Law - Immunology & Infectious Disease Graduate Student

Folake Ojo - Undergraduate Student

Meg Potter - Research Technician

Qian Qi - Immunology & Infectious Disease Graduate Student

Nisibeta Sahu - Biochemistry & Molecular Biology Grad Student

Elizabeth Walsh - Pathobiology Graduate Student

Shengli Hao......California Institute of Technology

Angela Fischer...... Johns Hopkins University School of Medicine

Nawel Mahrour......Stowers Institute for Medical Research

Jason Mercer......National Institute for Environmental Health Sciences, NIH

Melanie Ragin…. Johns Hopkins University School of Medicine

Regulation of immune response by intracellular signaling events.

We are interested in the role of Tyrosine Kinases (TKs) in regulating the immune response, with the goal of using this information to manipulate immune responses. We are specifically interested in the Tec families of nonreceptor TKs.

Regulation of T cell activation and function by Tec family kinases.

Regulation of T cell activation, differentiation and allergic asthma induction by Tec family kinases

Itk is a member of the Tec family of tyrosine kinases. Mice lacking Itk have T-cell defects, including reduced intracellular calcium increases during T cell activation and defective Th2 development. Understanding the specific downstream activities of these kinases is crucial to understanding how they impact lymphoid activation and development.

We have recently shown that the SH3 domain functionally interacts with the Proline Rich region of ITK, regulating both basal and activation induced kinase activity. We have also recently shown that mice lacking ITK a resistant to developing immunological symptoms of allergic asthma, a disease primarily driven by Th2 type T cells. Finally, we have recently shown that Tec kinases regulate the activation of the transcription factor Serum Response Factor (SRF), and that calcium mediated pathways differentially regulate the activation of SRF and the transcription factor NFAT, such that SRF has a lower requirement for calcium, while NFAT is absolutely dependent on calcium increase, regulated by Tec kinases. We are currently pursuing the signaling pathways regulated by Tec family kinases in vitro and in vivo, using the Th2 mediated disease allergic asthma as a model. Our recent data suggest that Itk controls the development of allergic asthma by regulating the development of Th2 responses, but also by regulating the ability of T cells to migrate into the lung.

Regulation of T cell development by Tec family kinases

We have recently shown that in the absence of Itk, a population of CD8 + T cells that have a memory phenotype (CD8 + CD44 + CD122 hi ) predominates. Our analysis of these cells indicate that they develop in the absence of direct signaling by Itk since they are present in transgenic mice carrying a mutant Itk with no kinase domain. We also showed that these cells have intrinsic innate immune function as the carry preformed message for the cytokine IFN g , and can this cytokine in response to IL-12/IL-18 stimulation. Our data suggest that these cells allow Itk null mice to effectively respond to infection with L. monocytogenes or exposure to LPS by secretion of IFN g . Confirming this, our experiments show that transfer of these cells rescues IFN g null mice during Listeria infection. We are continuing to study the function and behavior of this population of memory T cells with innate function.

Regulation of Mast cell activation and function by Tec family kinases

Itk is also expressed in mast cells, and has been shown to be activated when IgE interacts with the receptor for IgE (Fc e R) in these cells. Our recent experiments have started to examine the role of Itk in regulating the response of these cells to stimulation via the Fc e R. These experiments have implicates for the control of allergic responses, as well as those disease in which mast cells play a critical role.

(Selected)

Hu J, Sahu N, Walsh E and August A . Memory phenotype CD8 + T-cells with innate function selectively develop in the absence of active Itk . Eur. J. Immunol. In press (2007).

Qi Q and August A. Keeping the (kinase) party going: SLP-76 and ITK dance to the beat. Science STKE. 396:pe39. (2007).

Boonyarattanakalin S, Hu J, Dykstra-Rummel SA, August A and Peterson BR. Endocytic Drug Delivery Mediated by a Synthetic Cell Surface Receptor. J. Amer. Chem. Soc. 129, 268-9 (2007).

Qi Q, Sahu N and August A . Tec kinase Itk forms membrane clusters specifically in the vicinity of recruiting receptors. J. Biol. Chem 281, 38529-38534 (2006).

Hao S, Qi Q, Hu J and August A . A kinase independent function for Tec kinase ITK in regulating antigen receptor induced Serum Response Factor activation. Febs. Letts. 580:2691-2697 (2006).

¶ FerraraTJ, ¶ Mueller C, ¶ Sahu N, Ben-Jebria A, and August A . Reduced airway hyperresponsiveness and Tracheal responses during allergic asthma in mice lacking tyrosine kinase ITK. J. Allergy & Clin. Immunol. 117:780-6 (2006) ¶ equal contributors.

Ragin MJ, Sahu N and August A. Differential regulation of SEB induced cytokines by CD1d restricted NKT cells. Infec. & Imm. 74:282-8 (2006).

Ragin MJ, Hu J, Henderson AJ and August A. A role for the Tec family kinase ITK in regulating SEB induced Interleukin-2 production in vivo via the JNK pathway. BMC Immunology 6:19 (2005).

Hao S and August A. Actin depolymerization transduces the strength of B cell Receptor stimulation. Mol. Biol. Cell 16:2275-2284, (2005).

¶ Mercer JC, ¶ Ragin MJ, August A. Natural killer T cells: Rapid responders controlling immunity and disease. Int. J. Biochem. & Cell Biol . 37:1337-1343 (2005) ¶ equal contributors.

Fischer AM, Mercer JC, Iyer A, Ragin MJ, August A. Regulation of CXC chemokine receptor 4-mediated migration by the Tec family tyrosine kinase ITK. J Biol Chem. 279:29816-20, (2004)

Hao S, Kurosaki T, August A. Differential regulation of NFAT and SRF by the B cell receptor via a PLCgamma-Ca(2+)-dependent pathway. EMBO J. 22:4166-77, (2003)

Mueller C, August A. Attenuation of immunological symptoms of allergic asthma in mice lacking the tyrosine kinase ITK. J Immunol. 170:5056-63, (2003)

Woods ML, Kivens WJ, Adelsman MA, Qiu Y, August A, Shimizu Y. A novel function for the Tec family tyrosine kinase Itk in activation of beta 1 integrins by the T-cell receptor. EMBO J. 20:1232-44, (2001)