A decrease in oxygen availability (hypoxia) can be encountered both in physiological (e.g. high altitude) and pathological conditions (e.g. cardio-pulmonary diseases and cancer). Although hypoxia is usually associated with a poor outcome in several human disorders, the basic mechanisms by which the different cell types involved in the progression of the disease respond to the change in O2 availability are still poorly understood. Immune cells participate in many disease states and their functionality affects the remission or amelioration of the pathology. Various in vitro studies have indicated that hypoxia can inhibit the function of the host immune cells. While the mechanisms whereby hypoxia inhibits T cell activity are not well understood, the downstream effects of hypoxia on other cell types have been extensively studied. Thus we know that inhibition of K channel activity is one of the early events that occur following hypoxia and which eventually leads to changes in cellular function. K channels encoded by the Kv1.3 gene are expressed in T lymphocytes and control membrane potential and cell activity. Preliminary data indicate that native (in human T lymphocytes) and recombinant Kv1.3 channels are inhibited by hypoxia. Inhibition of these channels has been shown to inhibit T cell activation. Indeed, further preliminary evidence indicates that hypoxia inhibits Ca 2+ mobilization and proliferation in T lymphocytes. Therefore we hypothesize that the effect of hypoxia on T cell function is in part mediated by the ability of hypoxia to inhibit Kv1.3 channels. The proposed research aims to study the effect of hypoxia on Kv1.3 channel activity in T cells and to determine the functional implications of their hypoxic-inhibition. Experiments will be also performed to identify the signaling pathways mediating the oxygen sensitivity of Kv1.3 channels in T cells. A combination of electrophysiological, immunological and molecular biological techniques will be used. Findings from the proposed studies will provide new insights into the molecular basis of the immune response in hypoxia and will further our understanding of the ionic mechanisms of hypoxia-mediated changes in T cell function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095286-05
Application #
7198061
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2003-04-01
Project End
2009-03-30
Budget Start
2007-04-01
Budget End
2009-03-30
Support Year
5
Fiscal Year
2007
Total Cost
$256,240
Indirect Cost
Name
University of Cincinnati
Department
Physiology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Chimote, Ameet A; Balajthy, Andras; Arnold, Michael J et al. (2018) A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment. Sci Signal 11:
Conforti, Laura (2017) Potassium channels of T lymphocytes take center stage in the fight against cancer. J Immunother Cancer 5:2
Chimote, Ameet A; Hajdu, Peter; Sfyris, Alexandros M et al. (2017) Kv1.3 Channels Mark Functionally Competent CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer. Cancer Res 77:53-61
Chimote, Ameet A; Hajdu, Peter; Kottyan, Leah C et al. (2016) Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype. J Autoimmun 69:86-93
Hajdu, Peter; Martin, Geoffrey V; Chimote, Ameet A et al. (2015) The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin. Mol Biol Cell 26:1640-51
Chimote, Ameet A; Hajdu, Peter; Kucher, Vladimir et al. (2013) Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells. J Immunol 191:6273-80
Hajdu, Péter; Chimote, Ameet A; Thompson, Tyler H et al. (2013) Functionalized liposomes loaded with siRNAs targeting ion channels in effector memory T cells as a potential therapy for autoimmunity. Biomaterials 34:10249-57
Kuras, Zerrin; Kucher, Vladimir; Gordon, Scott M et al. (2012) Modulation of Kv1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex. Am J Physiol Cell Physiol 302:C1504-12
Conforti, Laura (2012) The ion channel network in T lymphocytes, a target for immunotherapy. Clin Immunol 142:105-6
Martin, Geoffrey V; Yun, Yeoheung; Conforti, Laura (2012) Modulation of T cell activation by localized Kýýý accumulation at the immunological synapse--a mathematical model. J Theor Biol 300:173-82

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