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Publication
Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway
Inflammation.
Authors Healey DCC, Cephus JY, Barone SM, Chowdhury NU, Dahunsi DO, Madden MZ, Ye X, Yu
X, Olszewski K, Young K, Gerriets VA, Siska PJ, Dworski R, Hemler J, Locasale
JW, Poyurovsky MV, Peebles RS, Irish JM, Newcomb DC, Rathmell JC
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Journal of immunology (Baltimore, Md. : 1950)
Year 2021
Date Published 3/1/2021
Volume : Pages 206 : 1127 - 1139
PubMed Reference 33558372
Abstract T effector cells promote inflammation in asthmatic patients, and both Th2 and
Th17 CD4 T cells have been implicated in severe forms of the disease. The
metabolic phenotypes and dependencies of these cells, however, remain poorly
understood in the regulation of airway inflammation. In this study, we show the
bronchoalveolar lavage fluid of asthmatic patients had markers of elevated
glucose and glutamine metabolism. Further, peripheral blood T cells of
asthmatics had broadly elevated expression of metabolic proteins when analyzed
by mass cytometry compared with healthy controls. Therefore, we hypothesized
that glucose and glutamine metabolism promote allergic airway inflammation. We
tested this hypothesis in two murine models of airway inflammation. T cells from
lungs of mice sensitized with Alternaria alternata extract displayed genetic
signatures for elevated oxidative and glucose metabolism by single-cell RNA
sequencing. This result was most pronounced when protein levels were measured in
IL-17-producing cells and was recapitulated when airway inflammation was induced
with house dust mite plus LPS, a model that led to abundant IL-4- and
IL-17-producing T cells. Importantly, inhibitors of the glucose transporter 1 or
glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell
cytokine production, and airway hyperresponsiveness as well as augmented the
immunosuppressive properties of dexamethasone. These data show that T cells
induce markers to support metabolism in vivo in airway inflammation and that
this correlates with inflammatory cytokine production. Targeting metabolic
pathways may provide a new direction to protect from disease and enhance the
effectiveness of steroid therapy.




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