An immune modulatory role for the fes proto-oncogene
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Authors
Alotaibi, Faizah
Date
2015-07-21
Type
thesis
Language
eng
Keyword
fes oncogene , immune system
Alternative Title
Abstract
The Fes protein tyrosine kinase is abundantly expressed in phagocytic immune cells, including
tumor associated macrophages. Fes knockout mice (fes-/-) display enhanced sensitivity to LPS,
and this was shown to be associated with increased NF-κB signaling and TNFα production from
fes-/- macrophages. Interestingly, tumor onset in the mouse mammary tumor virus (MMTV-Neu)
transgenic mouse model of breast cancer is significantly delayed in fes-/- mice, and this was
associated with increased frequency of CD11b+ myeloid and CD3+ T cells in the premalignant
mammary glands. Recent studies have also implicated Fes in cross-talk between MHC-I and the
NF-κB and IRF-3 pathways in macrophages. Signal 3, the production of inflammatory cytokines
and Type I interferons downstream of NF-κB and IRF-3 pathways in antigen presenting cells, is
considered an important component of T-cell activation, after engagement of T cell receptor by
MHC presented antigen (Signal 1) and co-receptors by their ligands (Signal 2).
Using a lymphocytic choriomeningitis virus (LCMV) model of immune activation, I
show that LPS stimulated fes-/- macrophages promote more robust activation of LCMV antigenspecific
CD8+ T cells than wild type macrophages (fes+/+). Furthermore, LPS stimulated fes-/-
macrophages showed increased phosphorylation of NF-B and IRF-3. I also showed that Fes colocalizes
with MHC-I in dynamic vesicular structures within macrophages. These observations
are consistent with a model where Fes regulates Signal 3 in antigen presenting cells through roles
in cross-talk between MHC-I and the NF-kB and IRF-3 signaling pathways. This suggests that
Fes plays an immune checkpoint role at the level of Signal 3, and that Fes inhibition could
promote tumor immunity through increased Signal 3 driven T cell activation.
Description
Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2015-07-13 16:20:30.348
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.