Generation of adaptive immune responses requires highly regulated migration and homing patterns are dictated not only by T cell receptor (TCR) engagement, but also by repertoires of adhesion and chemokine receptors on the cell surface. Chemokines and their receptors play essential roles in the regulation of T cell polarization, migration, adhesion, development, survival and proliferation. We have shown that the Abl family kinases, Abl and Arg, are activated by and regulate proximal signaling downstream of both the TCR and pre- TCR, and that conditional knockout mice lacking Abl and Arg in T cells exhibit impaired CD8+ T cell expansion upon bacterial infection. Abl/Arg double null T cells have markedly decreased TCR-induced signaling, proliferation, and cytokine production. We have now uncovered a critical role for Abl kinases in chemokine signaling in T cells. We found that Abl kinases are activated in response to chemokine stimulation and are required for chemokine-induced polarization and migration. Consistent with these findings, accumulating reports show that a pharmacological inhibitor of the Abl kinases is effective in the treatment of inflammatory conditions that involve T cell hyper activation. We hypothesize that Abl kinases modulate signals from chemokine receptors, thereby affecting T cell migration and inflammatory resonses and may be useful targets for the treatment of immune disorders promoted by T cell hyper activation. To test this hypothesis we propose the following aims: 1) Define the role of Abl kinases in chemokine-induced T cell polarization and migration. To this end we will A) elucidate the requirement for Abl kinases at distinct stages of T lymphocyte trafficking;B) identify Abl kinase targets critical for chemokine responses;and C) identify changes in the miRNA profile of chemokine- stimulated T cells and establish whether the Abl tyrosine kinases are involved in this process. 2) Determine whether Abl kinases regulate chemokine-mediated inflammatory responses in vivo. To this end we will employ T cell-conditional Abl/Arg knockout mice developed in our laboratory in order to: A) determine whether Abl kinases play a role in asthma development through the regulation of T cell-mediated functions;and B) determine whether pharmacological inhibition of the Abl kinases with a novel allosteric inhibitor impairs allergic asthma in a mouse model. These studies will uncover Abl-dependent pathways important for chemokine and TCR signaling and establish new therapeutic uses for Abl kinase inhibitors in the modulation of immune responses for the treatment of pathological conditions associated with T cell hyper activation.

Public Health Relevance

The finding that Abl tyrosine kinases are required for signaling downstream of the TCR and chemokine receptors has revealed a potential use for inhibitors of these kinases in the treatment of pathological conditions that involve hyper activation of T cell function such as T cell malignancies and asthma. Moreover, because inhibition of Abl kinases results in immune suppressive effects that diminish the normal T cell responses against pathogens, it is necessary to define the mechanisms whereby Abl kinases regulate T cell function. Results from the proposed studies will uncover novel roles for Abl kinases in the T cell response to antigens and chemokines, and establish new therapeutic avenues for Abl kinase inhibitors in the modulation of immune responses.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI056266-09
Application #
8683068
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Mallia, Conrad M
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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