Progress 07/01/05 to 06/30/10
Outputs
OUTPUTS: The T cell immune response is critical for the proper control of microbial infections. The type of immune response that is generated is dependent on different types of T cells; Th1 cells generate defenses against viruses, intracellular bacteria and arising tumors, Th2 cells generate defenses against certain parasites, viruses and bacteria, while Th17 cells generate defenses against extracellular bacteria and certain parasites. Th1, Th2 and Th17 cells are also involved in certain autoimmune diseases such as arthritis, MS (Th1) and allergies and asthma (Th2, Th17). Manipulating these cells will allow us to tailor specific immune responses to specific conditions. Mast cells are also critical in controlling parasitic infections, are involved in the development of asthma, and are the cells responsible for allergies. We have been pursuing our analysis of the role of the tyrosine kinase ITK, and the related kinase Txk, in T cell activation and function as well as in Mast cell function. Using genetically manipulated animals, we have continued our studies on the function of ITK and Txk. We have found that mice lacking ITK have development of allergic asthma. We have also found that mice lacking ITK develop a population of CD8+ and CD4+ T cells that have different properties to conventional T cells. These "memory phenotype T cells with innate function" or non-conventional T cells develop in the absence of Itk. More importantly, these cells rapidly secrete cytokines upon stimulation and provide enhanced protection against Listeria infection. Also apparent from this analysis is that ITK is required for the development of conventional T cells. More recently, we have found that mice lacking ITK have enhanced development of a specific population of gamma delta T cells that secretes elevated levels of the Th2 cytokine IL-4 and drive the production of IgE. More importantly these cells have a specific gamma delta T cell receptor that suggests they have critical function in vivo. In collaboration with Dr. Pamela Schwartzberg at the NIH, we have also shown that the absence of ITK specifically affects Th17 mediated production of IL17A, but not IL17F. Since IL17A is implicated in the development of allergic asthma, these data support our previous work on the role of ITK in regulating this disease. We have also shown that the related kinase Txk can rescue the ability of T cell lacking ITK to become Th2 cells and secrete IL-4. We have also extended our work on the immune response to the bacterial toxin SEB and found NKT cells may provide a protective response to exposure to bacterial superantigens such as SEB. In addition, we have shown that eosinophils, an innate immune cell, are required for the recruitment of T cells into the lungs during the development of allergic asthma. Also, of interest is our finding that mast cells lacking Itk secrete elevated levels of cytokines, but have normal degranulation patterns. Overall our investigations should point to novel strategies to manipulate Th1, Th2 and Th17 cell responses in the immune response against pathogenic insults and autoimmune diseases. PARTICIPANTS: Avery August (Veterinary & Biomedical Sciences) TARGET AUDIENCES: State of Pennsylvania Citizens and health decision makers, national and international Health decision makers. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
This research should lead to novel ways of manipulating the immune system during vaccination and infections in animals and humans, as well as manipulating T cells, eosinophils and mast cells that cause diseases such as in allergy and asthma, or are involved in parasitic infections.
Publications
- Powers, P. 2010. Physical interactions of Itk with itself and other proteins in the TCR signaling cascade. B.S. Schreyers Honor College Thesis in Immunology & Infectious Disease. The Pennsylvania State University, University Park, PA. 27 pp.
- Khong, H.H.M. 2010. Role of Tec family kinases in regulating MAP kinases. B.S. Schreyers Honor College Thesis in Immunology & Infectious Disease. The Pennsylvania State University, University Park, PA. 30 pp.
- Neely, A. 2010. A gene network analysis of T cell development. B.S. Schreyers Honor College Thesis in Animal Bioscience. The Pennsylvania State University, University Park, PA. 32 pp.
- Mercer, J., Q. Qi, L.F. Mottram, A. Iyer, M-K. Law, J.L. Morales, D. Bruce, H. Shirai, H. Yamazaki, B.R. Peterson and A. August. 2009. Chemico-genetic identification of the actin binding protein Drebrin as a regulator of extracellular calcium uptake. Int. J. Biochem. & Cell Biol. 42:337-345.
- He, S., S. Ni, S. Hegde, X. Wang, D.R. Sharda, A. August, R.F. Paulson, and P.A. Hankey. 2010. Activation of the N-terminally truncated form of the Stk receptor tyrosine kinase, Sf-Stk, by Friend virus encoded gp55 is mediated by cysteine residues in the ecotropic domain of gp55 and the extracellular domain of Sf-Stk. J. Virol. 84:2223-35.
- Natarajan, M., A. August, A.J. Henderson. 2010. Combinatorial Signals from CD28 differentially regulate Human Immunodeficiency Virus transcription in T cells. J. Biol. Chem. 285:17338-47.
- Khanna, P., T. Yunkunis, H.S. Muddana, H.-H. Peng, A. August, and C. Dong. 2010. Regulation of VE-cadherin Disassembly via p38 MAP Kinase phosphorylation during Melanoma Transendothelial Migration. (2010) Am. J. Phys.-Cell Phys. 298:C1140-50.
- Hu, J., Q. Qi, and A. August. 2010. Itk derived signals regulate the expression of Th-POK and controls the development of CD4+ T cells. PLOS One. 5:e8891.
- Walsh, E.R., K. Stokes and A. August. 2010. Role of Eosinophils in allergic airway inflammation. Discovery Medicine. 9:357-62.
- Xia, M., Q. Qi, Y. Jin, D. Wiest, A. August, and N. Xiong. 2010. Differential roles of ITK-mediated TCR signals in tissue-specific localization and maintenance of skin intraepithelial T cells. J. Immunol. 184:6807-14.
- Sahu, N., J. L. Morales, D. Fowell and A. August. 2010. Modeling susceptibility versus resistance in allergic airway disease reveals regulation by Tec kinase Itk. PLOS One. 5:e11348.
- Mercer, J.C. 2005. 3,5-Bistrifluoromethyl Pyrazole (BTP) compounds and regulation of Store Operated Calcium Channels by the Actin binding protein Drebrin. Ph.D. Thesis. The Pennsylvania State University, University Park, PA. 161 pp.
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Progress 10/01/08 to 09/30/09
Outputs
OUTPUTS: The T cell immune response is critical for the proper control of microbial infections. The type of immune response that is generated is dependent on different types of T cells; Th1 cells generate defenses against viruses, intracellular bacteria and arising tumors, Th2 cells generate defenses against certain parasites, viruses and bacteria, while Th17 cells generate defenses against extracellular bacteria and certain parasites. Th1, Th2 and Th17 cells are also involved in certain autoimmune diseases such as arthritis, MS (Th1) and allergies and asthma (Th2, Th17). Manipulating these cells will allow us to tailor specific immune responses to specific conditions. Mast cells are also critical in controlling parasitic infections, are involved in the development of asthma, and are the cells responsible for allergies. We have been pursuing our analysis of the role of the tyrosine kinase ITK, and the related kinase Txk, in T cell activation and function as well as in Mast cell function. Using genetically manipulated animals, we have continued our studies on the function of Txk in vivo, particularly in the development of allergic asthma. We have found that mice lacking ITK have enhanced development of a specific population of gamma delta T cells that secretes elevated levels of the Th2 cytokine IL-4 and drive the production of IgE. More importantly these cells have a specific gamma delta T cell receptor that suggests they have critical function in vivo. In collaboration with Dr. Pamela Schwartzberg at the NIH, we have also shown that the absence of ITK specifically affects Th17 mediated production of IL17A, but not IL17F. Since IL17A is implicated in the development of allergic asthma, these data support our previous work on the role of ITK in regulating this disease. Examining the structure of ITK, we have also shown that ITK has a specific structure in cells that was not previously predicted based on its individual domains. Finally, in collaboration with Dr. Margherita Cantorna (Veterinary & Biomedical Sciences, Penn State), we showed that the vitamin D receptor is not required for immune responses against the food borne pathogen Listeria monocytogenes. Overall our investigations should point to novel strategies to manipulate Th1, Th2 and Th17 cell responses in the immune response against pathogenic insults and autoimmune diseases. PARTICIPANTS: Avery August TARGET AUDIENCES: State of Pennsylvania Citizens and health decision makers, national and international Health decision makers PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
This research should lead to novel ways of manipulating the immune system during vaccination and infections in animals and humans, as well as manipulating T cells and mast cells that cause diseases such as in allergy and asthma, or are involved in parasitic infections.
Publications
- Qi, Q., M. Xia, A. Iyer, E. Hicks, N. Xiong, and A. August. 2009. Enhanced development of CD4+ T cells in the absence of Itk results in elevated IgE production. Blood 114:564-71.
- Sahu, N. and A. August. 2009. Itk inhibitors in inflammation and immune-mediated disorders. Curr. Top. Med. Chem. 9:690-703.
- August, A. 2009. ITK finds another (dance) partner...TFII-I. Eur. J. Immunol. 39:2354-7.
- Bruce, D., A. August, M. A. McDowell, and M. T. Cantorna. 2009. Vitamin D receptor is not required for primary or secondary immune responses to Listeria monocytogenes. Int. Immunol. 21:113-22.
- Soni, S., B.T. Lin, A. August, R. I. Nicholson, K. H. Kirsch. 2009. Expression of a phosphorylated p130Cas substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells. J. Cell. Biochem. 107:364-75.
- Qi, Q.and A. August. 2009. The Tec family kinase Itk exists as a folded monomer in vivo. J. Biol. Chem. (In Press).
- J. Gomez-Rodrigues, N. Sahu, R. Handon, T.S. Davidson, S.M. Anderson, M.R. Kirby, A. August, and P.L. Schwartzberg. 2009. Itk couples TCR activation to expression of IL17A via regulation of NFATc1. Immunity 31:1-11.
- Qi, Q. 2009. Role of Itk in the development of innate T cells. Ph.D. Thesis. The Pennsylvania State University, University Park, PA. 121 pp.
- Walsh, E. R. 2009. Eosinophil functions in the development of allergic asthma. Ph.D. Thesis. The Pennsylvania State University, University Park, PA. 126 pp.
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Progress 10/01/07 to 09/30/08
Outputs
OUTPUTS: The T cell immune response is critical for the proper control of microbial infections. The type of immune response that is generated is dependent on different types of T cells; Th1 cells generate defenses against viruses, bacteria and arising tumors while Th2 cells generate defenses against certain parasites, viruses and bacteria. Th1 and Th2 cells are also involved in certain autoimmune diseases such as arthritis, MS (Th1) and allergies and asthma (Th2). Manipulating these cells will allow us to tailor specific immune responses to specific conditions. Mast cells are also critical in controlling parasitic infections, are involved in the development of asthma, and are the cells responsible for allergies. We have been pursuing our analysis of the role of the tyrosine kinase ITK, and the related kinase Txk, in T cell activation and function as well as in Mast cell function. Using genetically manipulated animals, we have continued our studies on the function of Txk in vivo, particularly in the development of allergic asthma. We have found that mice lacking ITK are defective in developing naive CD4+ T cells, but have normal levels of "memory phenotype CD4+ T cells with innate function". More importantly, these cells rapidly secrete cytokines upon stimulation. These data have implications for manipulation of the T cell immune response by targeting this kinase. We have also shown that the related kinase Txk can rescue the ability of T cell lacking Itk to become Th2 cells and secrete IL-4. In addition, we have shown that eosinophils, an innate immune cell, are required for the recruitment of T cells into the lungs during the development of allergic asthma. Finally, we have show that mast cells lacking Itk secrete elevated levels of cytokines, but have normal degranulation patterns. Overall our investigations should point to novel strategies to manipulate Th1 and Th2 cell responses, as well as mast cell functions, in the immune response against pathogenic insults and autoimmune diseases. PARTICIPANTS: Avery August (Veterinary & Biomedical Sciences) TARGET AUDIENCES: State of Pennsylvania Citizens and health decision makers, national and international Health decision makers. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
This research should lead to novel ways of manipulating the immune system during vaccination and infections in animals and humans, as well as manipulating T cells and mast cells that cause diseases such as in allergy and asthma, or are involved in parasitic infections.
Publications
- Sahu, N. 2008. Regulation of T helper cell responses and allergic asthma by tec kinases. Itk and Txk Ph.D. Thesis The Pennsylvania State University, University Park, PA. 209 pp.
- Sahu, N., C. Mueller, A. Fischer, and A. August. 2008. Differential Sensitivity to Itk Kinase Signals for T Helper 2 Cytokine Production and Chemokine-Mediated Migration. J. Immunol. 180:3833-8.
- Readinger, J. A., G. M. Schiralli, J. K. Jiang, C. J. Thomas, A. August, A. J. Henderson, and P. L. Schwartzberg. 2008. Selective Targeting of ITK Blocks Multiple Steps of HIV Replication. Proc Natl Acad Sci U S A. 105:6684-9.
- Hu, J. and A. August. 2008. Naive and Innate Memory Phenotype CD4+ T Cells Have Different Requirements for Active Itk for Their Development. J. Immunol. 180:6544-52.
- Walsh, E.R., N. Sahu, J. Kearley, E. Benjamin, B. H. Kang, A. Humbles, and A. August. 2008. Strain-Specific Requirement for Eosinophils in the Recruitment of T Cells to the Lung During the Development of Allergic Asthma. J. Exp. Med. 205:1285-92.
- Iyer, A. S. and A. August. 2008. The Tec Family Kinase, IL-2-inducible T cell Kinase, Differentially Controls Mast Cell Responses. J. Immunol. 180:7869-77.
- Strasner, A. B., M. Natarajan, T. Doman, D. Key, A. August, and A. J. Henderson. 2008. The Src Kinase Lck Facilitates Assembly of HIV-1 at the Plasma Membrane. J. Immunol. 181:3706-13.
- Sahu, N., A. M. Venegas, D. Jankovic, W. Mitzner, J. Gomez-Rodriguez, J.L. Cannons, C. Sommers, P. Love, A. Sher, P.L. Schwartzberg, and A. August. 2008. Selective Expression Rather than Specific Function of Txk and Itk Regulate Th1 and Th2 Responses. J. Immunol. 181:6125-31.
- Hu, J. 2008. Role of Tec Family Kinase Itk in Regulating the Development of T Cell Subsets. Ph.D. Thesis. The Pennsylvania State University, University Park, PA. 163pp.
- Iyer, A. 2008. Role of Tec Family Kinases Itk and btk in FcERI Mediated Mast Cell Signaling. Ph.D. Thesis. The Pennsylvania State University, University Park, PA. 163 pp.
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Progress 01/01/07 to 12/31/07
Outputs
OUTPUTS: The T cell immune response is critical for the proper control of microbial infections. The type of immune response that is generated is dependent on different types of T cells; Th1 cells generate defenses against viruses, bacteria and arising tumors while Th2 cells generate defenses against certain parasites, viruses and bacteria. Th1 and Th2 cells are also involved in certain autoimmune diseases such as arthritis, MS (Th1) and allergies and asthma (Th2). Manipulating these cells will allow us to tailor specific immune responses to specific conditions. Mast cells are also critical in controlling parasitic infections, are involved in the development of asthma, and are the cells responsible for allergies. We have been pursuing our analysis of the role of the tyrosine kinase ITK in T cell activation and function as well as in Mast cell function. Using genetically manipulated animals, we have continued our studies on the function of ITK in vivo, in particularly in the
development of allergic asthma, and in response to infection with Listeria monocytogenes. We have found that mice lacking ITK develop a population of CD8+ T cells that have different properties to conventional CD8+ T cells. These "memory phenotype T cells with innate function" or non-conventional CD8+ T cells develop in the absence of Itk. More importantly, these cells rapidly secrete cytokines upon stimulation and provide enhanced protection against Listeria infection. Also apparent from this analysis is that Itk is required for the development of conventional CD8+ T cells. In the absence of Itk, very few of these cells develop. These data have implications for manipulation of the T cell immune response by targeting this kinase. We have also worked in collaboration with Dr. Blake Peterson (Chemistry Department, PSU) to show that a novel synthetic receptor can deliver specific antibiotics in vivo and in vitro. We have also been working with Dr. Margherita Cantorna, showing that the
vitamin D receptor plays an important role in regulating the development of allergic asthma in mouse models of this disease. Overall our investigations should point to novel strategies to manipulate Th1 and Th2 cell responses, as well as mast cell functions, in the immune response against pathogenic insults and autoimmune diseases.
PARTICIPANTS: Avery August & Andrew Henderson (Veterinary & Biomedical Sciences)
TARGET AUDIENCES: State of Pennsylvania Citizens and health decision makers, national and international Health decision makers.
PROJECT MODIFICATIONS: Avery August was designated as PI upon the departure of Andrew Henderson.
Impacts
This research should lead to novel ways of manipulating the immune system during vaccination and infections in animals and humans, as well as manipulating T cells and mast cells that cause diseases such as in allergy and asthma, or are involved in parasitic infections.
Publications
- Wittke, A., A. Chang, M. Froicu, O.F. Harandi, V. Weaver, A. August, R. F. Paulson and M. T. Cantorna. 2007. Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch. Bioch. Biophys. 460(2):306-13.
- Qi, W., and A. August. 2007. Keeping the (kinase) party going: SLP-76 and ITK dance to the beat. Science STKE. 2007 Jul 24. http://www.ncbi.nlm.nih.gov
- Hu, J., N. Sahu, E. Walsh and A. August. 2007. Memory phenotype CD8+ T-cells with innate function selectively develop in the absence of active Itk. Eur. J. Immunol. 37:2892-9.
- Sun, M., S. M. Fuentes, K. Timani, D. Sun, C. Murphy, Y. Lin, A. August , M. N. Teng, and B. He. 2007. Akt plays a critical role in replication of non-segmented negative stranded RNA viruses. J. Virology. Epub 2007 Oct 24. http://jvi.asm.org
- Boonyarattanakalin, S., J. Hu, S.A. Dykstra-Rummel, A. August, and B. R. Peterson. 2007. Endocytic Drug Delivery Mediated by a Synthetic Cell Surface Receptor. J.Amer. Chem. Soc. 129:268-9
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Progress 01/01/06 to 12/31/06
Outputs
The T cell immune response is critical for the proper control of microbial infections. Different types of T cells are responsible for different types of immune responses; Th1 cells for defense against viruses, bacteria and arising tumors and Th2 cells for the immune response against certain parasites and viruses and against certain bacteria. Th2 cells are also involved in certain autoimmune diseases such as allergies and asthma. Manipulating these cells will allow us to tailor specific immune responses to specific conditions. Mast cells are also critical in controlling parasitic infections, are involved in the development of asthma, and are the cells responsible for allergies. We have been pursuing our analysis of the role of the tyrosine kinase ITK in T cell activation and function as well as in Mast cell function. Using genetically manipulated animals, we have continued our studies on the function of ITK in vivo, in particularly in the development of allergic
asthma, but also in response to exposure to a bacterial toxin. We have found that ITK can activate certain signaling pathways in a kinase domain independent function. Our data suggest that targeting the kinase domain of ITK may not guarantee inhibiting its function. We are testing this point in novel transgenic mice that we have generated. We have found that mice lacking ITK have reduced airway hyperresponsiveness (AHR) during the development of allergic asthma. In addition, disease in these mice can be rescued by transfer of normal T cells. We also found that PPAR delta ligands can reduced the development of AHR when given intranasally in mice. These results suggest that compounds that interact with PPAR delta, which are already on the market, may be useful for treating symptoms of allergic asthma. We have also extended our work on the immune response to the bacterial toxin SEB. We find that mice that lack NKT cells, a unique T cell population, have differential responses to SEB
exposure. Our data suggest that NKT cells may provide a protective response to exposure to bacterial superantigens such as SBE. We are continuing our analysis of the function of ITK in T cells and mast cells. Overall our investigations should point to novel strategies to manipulate Th1 and Th2 cell responses, as well as mast cell functions, in the immune response against pathogenic insults and autoimmune diseases.
Impacts
This research should lead to novel ways of manipulating the immune system during vaccination and infections in animals and humans, as well as manipulating T cells and mast cells that cause diseases such as in allergy and asthma, or are involved in parasitic infections.
Publications
- August, A., Mueller, C., Weaver, V., Polanco, T.A., Walsh, E.R., and Cantorna, M.T. 2006. Lipids, PPAR and Allergic Asthma. J. Nutr. 136:695-9.
- Ragin, M.J., Sahu, N., and August, A. 2006. Differential regulation of SEB induced cytokines by CD1d restricted NKT cells. Infec. & Imm. 74:282-8.
- Ferrara, T.J., Mueller, C., Sahu, N., Ben-Jebria, A., and August, A. 2006. Reduced airway hyperresponsiveness and Tracheal responses during allergic asthma in mice lacking tyrosine kinase ITK. J. Allergy & Clin. Immunol. 117:780-6.
- Hao, S., Qi, Q., Hu, J., and August, A. 2006. A kinase independent function for Tec kinase ITK in regulating antigen receptor induced Serum Response Factor activation. Febs. Letts. 580:2691-2697.
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Progress 01/01/05 to 12/31/05
Outputs
The T cell immune response is critical for the proper control of microbial infections. Different types of T cells are responsible for different types of immune responses; Th1 cells for defense against viruses, bacteria and arising tumors and Th2 cells for the immune response against certain parasites and viruses and against certain bacteria. Th2 cells are also involved in certain autoimmune diseases such as allergies and asthma. Manipulating these cells will allow us to tailor specific immune responses to specific conditions. Mast cells are also critical in controlling parasitic infections, are involved in the development of asthma, and are the cells responsible for allergies. We have been pursuing our analysis of the role of the tyrosine kinase ITK in T cell activation and function as well as in Mast cell function. Using genetically manipulated animals, we have continued our studies on the function of ITK in vivo, in particularly in the development of allergic
asthma, but also in response to exposure to a bacterial toxin. We have found that mice lacking ITK have reduced cytokine response upon exposure to the bacterial toxin SEB. However, these mice were still susceptible to toxic shock caused by this toxin. We have also found that mice lacking ITK exhibit reduced airway responses, cytokine responses and chemokine responses in our model of allergic asthma. We are continuing our analysis of the function of ITK in T cells and mast cells. Overall our investigations should point to novel strategies to manipulate Th1 and Th2 cell responses, as well as mast cell functions, in the immune response against pathogenic insults and autoimmune diseases.
Impacts
This research should lead to novel ways of manipulating the immune system during vaccination and infections in animals and humans, as well as manipulating T cells and mast cells that cause diseases such as in allergy and asthma, or are involved in parasitic infections.
Publications
- Mercer, J.C., Ragin, M.J. and August, A. 2005. Natural Killer T cells: Rapid responders controlling immunity and disease. Int. J. Biochem. & Cell Biol. 37:1337-1343.
- Ragin, M.J., Hu, J., Henderson, A.J. and August, A. 2005. 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.
- Ragin, M.J. 2005. Analysis of T and NKT cell Activation and Function in response to SEB in vivo. Ph.D. Thesis. The Pennsylvania State University, University Park, PA. 105 pp.
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