IP4 is a newly discovered second messenger that we identified to be critical for T cell development and activation. How IP4 transmits T cell receptor signals to induce thymocyte maturation remains unclear. Its chemical similarity to the membrane lipid PIP3 suggests that it co-regulates PIP3-effectors, including the serine/threonine kinase AKT. In this grant, we propose that AKT is an important effector pathway downstream of IP4 that contributes to the development of mature CD4 or CD8 T cells and regulatory T cells. We hypothesize that IP4 promotes AKT activity through release of active AKT from the membrane and by facilitating AKT binding to Calmodulin, a Ca2+ sensing regulator of protein function. To test this hypothesis, we present three specific aims. In the first, we will characterize AKT binding to IP4 and PIP3 individually and by competitive inhibition analysis. Second, we will determine how IP4 regulates AKT localization, activation and phosphorylation of downstream effectors. Lastly, we will examine the importance of Calmodulin binding on AKT function in vivo and determine its dependence on IP4. We hope that elucidating the mechanism by which IP4 regulates AKT activity will allow a better understanding of how developmental signals precisely and differentially induce AKT activation to promote the maturation of different T cell subsets. Our long term objective is to characterize how IP4 relays signals from T cell surface receptors to direct specific and protective immune responses.

Public Health Relevance

Itpks generate IP4, a novel second messenger that is required for T cell development and activation, and has also been genetically linked to autoimmunity. This proposal seeks to understand how IP4 regulation of the proto-oncogene AKT controls T cell function.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Prabhudas, Mercy R
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Dartmouth College
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Malik, Brian T; Byrne, Katelyn T; Vella, Jennifer L et al. (2017) Resident memory T cells in the skin mediate durable immunity to melanoma. Sci Immunol 2:
Hampsch, Riley A; Shee, Kevin; Bates, Darcy et al. (2017) Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer. Oncotarget 8:21806-21817
Li, Na; Xu, Wenwen; Yuan, Ying et al. (2017) Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Sci Rep 7:1485
Xu, Xiaolu; Wang, Xinxin; Todd, Elizabeth M et al. (2016) Mst1 Kinase Regulates the Actin-Bundling Protein L-Plastin To Promote T Cell Migration. J Immunol 197:1683-91
Westernberg, Luise; Conche, Claire; Huang, Yina Hsing et al. (2016) Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte ?-selection and renders it Notch-dependent. Elife 5:
Wang, Xinxin; Hills, Leonard Benjamin; Huang, Yina Hsing (2015) Lipid and Protein Co-Regulation of PI3K Effectors Akt and Itk in Lymphocytes. Front Immunol 6:117
Liu, Jun; Yuan, Ying; Chen, Wenna et al. (2015) Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A 112:6682-7
Clancy-Thompson, Eleanor; Perekslis, Thomas J; Croteau, Walburga et al. (2015) Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease. Cancer Immunol Res 3:956-67
Lubman, Olga Y; Cella, Marina; Wang, Xinxin et al. (2014) Rodent herpesvirus Peru encodes a secreted chemokine decoy receptor. J Virol 88:538-46
Wang, Xinxin; Boyken, Scott E; Hu, Jiancheng et al. (2014) Calmodulin and PI(3,4,5)P? cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production. Sci Signal 7:ra74

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